Controlled release pharmaceutical compositions comprising a fumaric acid ester

ABSTRACT

The present invention relates to controlled release pharmaceutical compositions comprising fumaric acid ester(s) as active substance(s). The compositions are suitable for use in the treatment of e.g. psoriasis or other hyperproliferative, inflammatory or autoimmune disorders and are designated to release the fumaric acid ester in a controlled manner so that local high concentrations of the active substance within the gastrointestinal tract upon oral administration can be avoided and, thereby, enabling a reduction in gastro-intestinal related side effects.

FIELD OF THE INVENTION

The present invention relates to controlled release pharmaceuticalcompositions comprising a fumaric acid ester as an active substance. Thecompositions are suitable for use in the treatment of e.g. psoriasis orother hyperproliferative, inflammatory or autoimmune disorders and aredesigned to release the fumaric acid ester in a controlled manner sothat local high concentrations of the active substance within thegastrointestinal tract upon oral administration can be avoided and,thereby, enabling a reduction in gastro-intestinal related side-effects.

BACKGROUND OF THE INVENTION

Fumaric acid esters, i.e. dimethylfumarate in combination withethylhydrogenfumarat have been used in the treatment of psoriasis formany years. The combination is marketed under the tradename Fumaderm®.It is in the form of tablets intended for oral use and it is availablein two different dosage strengths (Fumaderm® initial and Fumaderm®):

Fumaderm ® Initial Fumaderm ® Dimethylfumarate 30 mg 120 mgEthylhydrogenfumarate, 67 mg  87 mg calcium salt Ethylhydrogenfumarate, 5 mg  5 mg Magnesium salt Etylhydrogenfumarate,  3 mg  3 mg Zinc salt

The two strengths are intended to be applied in an individually baseddose regimen starting with Fumaderm® initial in an escalating dose, andthen after e.g. three weeks of treatment switching to Fumaderm®. BothFumaderm® initial and Fumaderm® are enteric coated tablets.

Another marketed composition is Fumaraat 120® containing 120 mg ofdimethylfumarate and 95 mg of calcium monoethylfumarate (TioFarma,Oud-Beijerland, Netherlands). In a recent publication (Litjens et al.Br. J. Clin. Pharmacol. 2004, vol. 58:4, pp. 429-432), thepharmacokinetic profile of Fumaraat 120® is described in healthysubjects. The results show that a single oral dose of Fumaraat 120® isfollowed by a rise in serum monomethylfumarate concentration and onlynegligible concentrations of dimethylfumarate and fumaric acid isobserved. The results indicate that dimethylfumarate is rapidlyhydrolyzed to monomethylfumarate in an alkaline environment, butaccording to the authors not in an acid environment. As the compositionis enteric coated, it is contemplated that the uptake of fumarate takesplace mainly in the small intestine, where dimethylfumarate beforeuptake is hydrolysed to the monoester due to an alkaline environment, orit may rapidly be converted due to esterases in the circulation.Furthermore, the study shows that t_(max) and C_(max) are subject tofood effect, i.e. t_(max) is prolonged (mean for fasted conditions is182 min, whereas for fed conditions mean is 361 min) [lag time is 90 minfor fasted and 300 min for fed] and C_(max) is decreased (fasted: 0.84mg/l, fed: 0.48 mg/l) by concomitant food-intake. Another study(Reddingius W. G. Bioanalysis and Pharmacokinetics of Fumarates inHumans. Dissertation ETH Zurich No. 12199 (1997)) in healthy subjectswith two tablets of Fumaderm® P forte revealed C_(max) values(determined as monoethyl- or monomethylfumarate) in a range from 1.0 to2.4 μg/ml and a t_(max) in a range of from 4.8 to 6.0 hours.

U.S. Pat. No. 6,277,882 and U.S. Pat. No. 6,355,676 discloserespectively the use of alkyl hydrogen fumarates and the use of certainfumaric acid mono alkyl ester salts for preparing micro tablets fortreating psoriasis, psoriatic arthritis, neurodermatitis and enteritisregionalis Crohn. U.S. Pat. No. 6,509,376 discloses the use of certaindialkyl fumarates for the preparation of pharmaceutical preparations foruse in transplantation medicine or the therapy of autoimmune diseases inthe form of micro tablets or pellets. U.S. Pat. No. 4,959,389 disclosecompositions containing different salts of fumaric acid monoalkyl esteralone or in combination with dialkyl fumarate. GB 1,153,927 relates tomedical compositions comprising dimethylmaleic anhydride and/ordimethylmaleic acid and/or a dimethylfumaric acid compounds. The Casereport “Treatment of disseminated granuloma annulare with fumaric acidesters” from BMC Dermatology, vol. 2, no. 5, 2002, relates to treatmentwith fumaric acid esters.

However, therapy with fumarates like e.g. Fumaderm® frequently givesrise to gastro-intestinal side effects such as e.g. fullness, diarrhea,upper abdominal cramps, flatulence and nausea.

Accordingly, there is a need to develop compositions comprising one ormore therapeutically or prophylactically active fumaric acid esters thatprovide an improved treatment with a reduction in gastro-intestinalrelated side effects upon oral administration.

Furthermore, the present commercially available products contain acombination of two different esters of which one of the esters (namelythe ethylhydrogenfumarate which is the monoethylester of fumaric acid)is present in three different salt forms (i.e. the calcium, magnesiumand zinc salt). Although each individual form may have its owntherapeutic profile it would be advantageous to have a much simplerproduct, if possible, in order to obtain a suitable therapeutic effect.

The present inventors contemplate that an improved treatment regimen maybe obtained by administration of a pharmaceutical composition that isdesigned to deliver the active substance in a controlled manner, i.e. ina manner that is prolonged, slow and/or delayed compared with thecommercially available product. Furthermore, it is contemplated thatinstead of using a combination of different fumaric acid esters, asuitable therapeutic response may be achieved by use of a single fumaricacid ester alone such as dimethylfumaric acid.

SHORT DESCRIPTION OF THE FIGURES

FIG. 1 shows an example of an in vitro dissolution profile of a capsuleprepared as described in example 5.

FIG. 2 shows an example of an in vitro dissolution profile of a sampleof a tablet (before the enteric coating is applied) prepared asdescribed in example 16.

FIG. 3 shows an example of an in vitro dissolution profile of a sampleof a tablet (before the enteric coating is applied) prepared asdescribed in example 17.

DISCLOSURE OF THE INVENTION

Accordingly, the present invention relates to a pharmaceuticalcomposition comprising as an active substance one or more fumaric acidesters selected from di-(C₁-C₅)alkylesters of fumaric acid andmono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceuticallyacceptable salt thereof, which—upon oral administration and incomparison to that obtained after oral administration of Fumaderm®tablets in an equivalent dosage—gives a reduction in GI(gastro-intestinal) related side-effects.

As mentioned above, the present inventors contemplate that a suitableway of reducing the gastro-intestinal related side-effects is byadministration of the active substance in the form of a controlledrelease composition.

Accordingly, the present invention relates in a further aspect to acontrolled release pharmaceutical composition for oral use comprising asan active substance one or more fumaric acid esters selected fromdi-(C₁-C₅)alkylesters of fumaric acid and mono-(C₁-C₅)alkylesters offumaric acid, or a pharmaceutically acceptable salt thereof, wherein therelease of the fumaric acid ester—when subjected to an in vitrodissolution test employing 0.1 N hydrochloric acid as dissolution mediumduring the first 2 hours of the test and then 0.05 M phosphate buffer pH6.5 as dissolution medium—is as follows:

within the first 3 hours after start of the test at the most about 70%w/w of the total amount of the fumaric acid ester contained in thecomposition is released, and/or

within the first 4 hours after start of the test at the most about 92%w/w of the total amount of the fumaric acid ester is released, and/or

within the first 5 hours after start of the test at the most about 94%w/w of the total amount of the fumaric acid ester is released, and/or

within the first 6 hours after start of the test at the most about 95%w/w of the total amount of the fumaric acid ester contained in thecomposition is released, and/or

within the first 7 hours after start of the test at the most about 98%w/w of the total amount of the fumaric acid ester contained in thecomposition is released, and/or

within the first 9 hours after start of the test at the most about 99%w/w of the total amount of the fumaric acid ester contained in thecomposition is released and/or

within the first 12 hours after start of the test at the most about 99%w/w of the total amount of the fumaric acid ester contained in thecomposition is released.

In the present context, a controlled release composition is acomposition that is designed to release the fumaric acid ester in aprolonged, slow and/or delayed manner compared to the release of thecommercially available product Fumaderm®, when tested under comparableconditions (e.g. for in vivo studies: dose equivalents, with or withoutstandardized meal etc., or for in vitro studies: dose equivalents,dissolution test apparatus and working conditions including e.g.composition, volume and temperature of dissolution medium employed,rotation speed etc.).

The release in vivo may be tested by measuring the plasma concentrationat predetermined time periods and thereby obtaining a plasmaconcentration versus time profile for the fumaric acid ester in questionor, if relevant, a metabolite thereof. (E.g. in the case ofdimethylfumarate, the active substance is envisaged to bemethylhydrogenfumarate, i.e. the monomethyl ester of fumaric acid).Furthermore, it is contemplated that metabolism already takes placewithin the gastro-intestinal tract or during passage of thegastro-intestinal mucosa, or upon first passage through the hepaticcirculation. Accordingly, when dimethylfumarate is administered, therelevant component to search for in the plasma may be the monomethylester and not the dimethylester of fumaric acid.

Other tests may also be used to determine or to give a measure of therelease of the active substance in vivo. Thus, animals (e.g. mice, rats,dogs etc.) may be used as a model. The animals receive the compositionsunder investigation and after specified periods of time, the animals aresacrificed and the content of the active ingredient (or metabolitethereof, if relevant) is determined in plasma or specific organs orextracted from the intestinal contents.

Another test involves the use of a specific segment of an animalintestine. The segment is placed in a suitable dissolution apparatuscontaining two compartments (a donor and a receiver) separated by thesegment, and the composition under investigation is placed in a suitablemedium in one compartment (the donor compartment). The composition willrelease the active substance that subsequently is transported across theintestinal segment. Accordingly, at suitable time intervals, theconcentration of the active substance (or, if relevant, the metabolite)is measured in the receiver compartment.

A person skilled in the art will be able to adapt the above-mentionedmethod to the specific composition.

With respect to in vitro methods, well-established methods areavailable, especially methods described by official monographs like e.g.United States Pharmacopeia (USP) or the European Pharmacopoeia. A personskilled in the art will know which method to choose and how to selectthe specific conditions to carry out the in vitro test. For instance,the USP prescribes in vitro tests be carried out at 37+/−1.0 such as37+/−0.5 degrees Celsius/Centigrade. A suitable dissolution test is, forexample as described in example 29, for capsules, wherein thedissolution profile is determined as described in the United StatesPharmacopoeia at 37° C. using a rotating basket at 100 rpm employing 0.1N hydrochloric acid as dissolution medium during the first 2 hours ofthe test and then followed by 0.05 M phosphate buffer pH 6.5 asdissolution medium for the remaining test period, and, for example asdescribed in example 30, for tablets wherein the dissolution profile isdetermined as described in the United States Pharmacopoeia at 37° C.using a paddle dissolution apparatus at 100 rpm employing 0.1 Nhydrochloric acid as dissolution medium during the first 2 hours of thetest and then followed by 0.05 M phosphate buffer pH 6.5 as dissolutionmedium for the remaining test period.

As mentioned above, the in vivo release of the active substance isprolonged, slow and/or delayed compared with the commercially availableFumaderm® composition. In the present context, the term “prolonged” isintended to indicate that the active substance is released during alonger time period than Fumaderm® such as at least during a time periodthat is at least 1.2 times, such as, e.g., at least 1.5 times, at least2 times, at least 3 times, at least 4 times or at least 5 times greaterthan that of Fumaderm®. Thus, if e.g. 100% of dimethylfumarate isreleased from Fumaderm® tablets 3 hours after the start of a suitabletest, then 100% of dimethylfumarate in a composition according to theinvention is released at least 3.6 hours after the start of a suitabletest.

In the present context the term “delayed” is intended to indicate thatthe release of the active substance starts at a later point in timecompared with that of Fumaderm® (such as at 30 min or more later suchas, e.g., 45 min or more later, 1 hour or more later or 1.5 hours ormore later, alternatively, that the initial release during the first 2hours is much less compared with that of Fumaderm® (i.e. less than 80%w/w such as, e.g., less than 70% w/w, less than 60% w/w or less than 50%of that of Fumaderm®).

As used in the present invention, a gastrointestinal (GI) side effectmay include, but is not limited to diarrhea, stomach ache, stomach pain,abdominal pain, abdominal cramps, nausea, flatulence, tenesmus,meteorism, an increased frequency of stools, a feeling of fullness andupper abdominal cramps.

In the present context, a reduction of GI related side effects isintended to denote a decrease in severity and/or incidence among a giventreated patient population, compared to the GI side effects observedafter administration of the composition according to the inventioncompared with that of Fumaderm®. A reduction in GI related side effectsaccording to this definition could thus be construed as a substantialreduction in incidence of any of the GI side effect listed above, suchas at least a 10% reduction in incidence or more preferably at least 20%reduction in incidence or even more preferable a more than 30% reductionin incidence. A reduction in GI related side effect can also beexpressed as a substantial reduction in severity in any of the GI sideeffects listed above, such as a reduction in severity and/or frequencyof diarrhea, stomach ache, stomach pain, abdominal pain, abdominalcramps, nausea, flatulence, tenesmus, meteorism, increased frequency ofstools, a feeling of fullness or upper abdominal cramps. The reductionof GI related side effects, as described above, can be monitored in aclinical trial setting, either comparing the administration of thecomposition according to the invention head on with Fumaderm® or withplacebo. In case of a placebo controlled trial, the incidence of GIrelated side effects in the patients receiving the composition accordingto the invention compared to the placebo group, can be compared tohistorical trials comparing Fumaderm® to placebo (see e.g. Altmeyer etal, J. Am. Acad. Dermatol. 1994; full reference: Altmeyer P J et al,Antipsoriatic effect of fumaric acid derivatives. Results of amulticenter double-blind study in 100 patients. J. Am. Acad. Dermatol.1994; 30:977-81). Typically, patients suffering from psoriasis areincluded in such a study, and typically more than 10% of the bodysurface area will be affected by psoriasis (severe psoriasis). However,patients in whom between 2 and 10 percent of the body surface area isaffected can also be included (moderate psoriasis). Patients can also beselected based on the psoriasis area severity index (PASI). Typically,patients within a certain range of PASI are included, such as between 10and 40, or such as between 12 and 30, or such as between 15 and 25.Patients with any type of psoriasis may be included (chronic plaquetype, exanthematic guttate type, pustular type, psoriatic erythrodermaor palmoplantar type), but in some cases only patients with the chronicplaque type are included. About 15 to 20 patients in each treatmentgroup (composition according to the invention and Fumaderm® or placebo)are sufficient in most cases, but more preferably about 30 to 50patients are included in each arm of the study. Total study duration canbe as short as one day to one week, but more preferably the study willrun for 8 weeks to 12 weeks or up to 16 weeks. The side effects can e.g.be assessed as the total number of times a certain side effect wasreported in each group (irrespective of how many patients haveexperienced the side effect), or the side effects can be assessed as thenumber of patients that have experienced a certain side effect a certainnumber of times, such as at least once or at least twice or at leastthree times during the duration of the study. Furthermore, the severityof a side effect can be monitored, or a certain severity of a sideeffect can be required for it to qualify as a side effect in the study.A convenient way of assessing the severity of a side effect is via avisual analogue (VAS) scale.

Active Substance

The active substance in a composition of the invention is any fumaricacid ester. In one embodiment of the invention the fumaric acid ester ispreferably selected from the group consisting of dimethylfumarate,diethylfumarate, dipropylfumarate, dibutylfumarate, dipentylfumarate,methyl-ethylfumarate, methyl-propylfumarate, methyl-butylfumarate,methyl-pentylfumarate, monomethylfumarate, monoethylfumarate,monopropylfumarate, monobutylfumarate and monopentylfumarate, includingpharmaceutically acceptable salts thereof.

In a specific embodiment of the invention, the fumaric acid ester is amono-(C₁-C₅)alkylester of fumaric acid that is present in the form of apharmaceutically acceptable salt. Suitable salts are e.g. metal saltssuch as a salt selected from alkali metal salts and alkaline earth metalsalts including sodium, potassium, calcium, magnesium or zinc salt.

The term (C₁-C₅)alkyl refers to a branched or un-branched alkyl grouphaving from one to five carbon atoms inclusive, such as methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl,2-methyl-1-propyl and pentyl.

In another embodiment, the composition according to the inventioncomprises dimethylfumarate as the active substance.

In a further embodiment, the composition according to the inventioncomprises monomethylfumarate as the active substance optionally in theform of a pharmaceutically acceptable salt like e.g. its sodium,potassium, calcium, magnesium and/or zinc salt.

In another embodiment, the composition according to the inventionconsists essentially of dimethylfumarate as the active substance.

In another embodiment, the composition according to the inventionconsists of dimethylfumarate as the active substance.

In a further embodiment, the composition according to the inventionconsists essentially of monomethylfumarate as the active substanceoptionally in the form of a pharmaceutically acceptable salt like e.g.its sodium, potassium, calcium, magnesium and/or zinc salt.

In a further embodiment, the composition according to the inventionconsists of monomethylfumarate as the active substance optionally in theform of a pharmaceutically acceptable salt like e.g. its sodium,potassium, calcium, magnesium and/or zinc salt.

In a further embodiment, the composition according to the inventioncomprises dimethylfumarate and monomethylfumarate (optionally in theform of a pharmaceutically acceptable salt like e.g. its sodium,potassium, calcium, magnesium and/or zinc salt) as the activesubstances, in a weight ratio between about 1:10 and about 10:1.

In a further embodiment, the composition according to the inventionconsists essentially of dimethylfumarate and monomethylfumarate(optionally in the form of a pharmaceutically acceptable salt like e.g.its sodium, potassium, calcium, magnesium and/or zinc salt) as theactive substances, in a weight ratio between about 1:10 and about 10:1.

In a further embodiment, the composition according to the inventionconsists of dimethylfumarate and monomethylfumarate (optionally in theform of a pharmaceutically acceptable salt like e.g. its sodium,potassium, calcium, magnesium and/or zinc salt) as the activesubstances, in a weight ratio between about 1:10 and about 10:1.

Cosmetic and/or Pharmaceutical Compositions

The problem the invention solves is related to the appearance ofgastro-intestinal side-effects upon oral administration of fumaric acidesters. By prolonging and/or delaying the release of the activesubstance from the composition it is envisaged that the localconcentration of the active substance at specific sites of thegastro-intestinal tract is reduced (compared with that of Fumaderm®)which in turn leads to a reduction in gastro-intestinal side-effects.Accordingly, compositions that enable a prolonged and/or a slow releaseof a fumaric acid ester as defined above are within the scope of thepresent invention.

Such compositions are well-known to the skilled artisan and include e.g.diffusion-controlled drug delivery systems, osmotic pressure controlleddrug delivery systems, erodible drug delivery systems etc. Moreover,there are pharmaceutical companies that based on a specific technology(such as mentioned above) can provide a specific composition withspecific release characteristics of the active substance. Accordingly, aperson skilled in the art will know how to obtain a suitable productonce he has realized a specific need in respect of a particular drugsubstance. By way of example, Eurand is one of such companies that offertechnical solutions in order to obtain a controlled releasepharmaceutical composition containing a specific active substance andhaving specific requirements with respect to the release of the activesubstance from the composition (see e.g. http://www.eurand.com). Anothercompany is MacroMed, Inc. that has developed a technology involving aso-called SQZgel™ (http://macromed.com, SQZgel™'s mechanism of action isa pH-sensitive polymer mixture combined with an outer coating. In theacidic environment of the stomach the polymer imbibes with water andswells, entrapping the drug. Upon entering the higher pH of theintestines, the polymer slowly shrinks, or “squeezes” at a “dialed-in”rate releasing the active composition in a sustained manner), or Egaleta/s that has a specific extrusion based technology(http://www.egalet.com, Key elements of the Egalet® technology are abiodegradable coat and a matrix, comprising the active drug, which issurface erodible, hydrophobic and composed of PEG-stearate. One of theEgalet® technologies is the 2K Egalet® constant release system, which isa 2-component production model consisting of coat and matrix. The drugis evenly distributed throughout the Egalet® matrix for constant releaseover time. Also of interest in the present context are technologies likee.g. the Eurand technologies Diffucaps (Drug release profiles arecreated by layering active drug onto a neutral core such as sugarspheres, crystals or granules followed by a rate-controlling, functionalmembrane. Diffucaps/Surecaps beads are small in size, approximately 1 mmor less in diameter. By incorporating beads of differing drug releaseprofiles into hard gelatin capsules, combination release profiles can beachieved), Diffutabs (The Diffutab technology incorporates a blend ofhydrophilic polymers that control drug release through diffusion anderosion of a matrix tablet), Minitabs (Eurand Minitabs are tiny (2 mm×2mm) tablets containing gel-forming excipients that control drug releaserate. Additional membranes may be added to further control releaserate), Orbexa (This technology produces beads that are of controlledsize and density with a defined-based granulation extrusion andspheronization techniques. The resultant beads can be coated withrelease rate controlling membranes for additional release rate controland may be filled into capsules or provided in sachet form) and SDS(Eurand's SDS technology uses functional polymers or a combination offunctional polymers and specific additives, such as composite polymericmaterials, to deliver a drug to a site of optimal absorption along theintestinal tract. In order to achieve this, Eurand first producesmultiparticulate dosage forms such as Diffucaps or Eurand Minitabs,which incorporate the active drug. These dosage forms are then coatedwith pH dependent/independent polymeric membranes that will deliver thedrug to the desired site. These are then filled into hard gelatincapsules).

Another interesting technology for use in formulating compositionsaccording to the present invention is the so-called MeltDose® technologyas described in WO 03/004001 (see http://www.lifecyclepharma.com.MeltDose® involves formulating solubilized, individual molecules intotablets. By formulating individual molecules, the primary limitation oforal absorption of drugs with low water-solubility is removed, and asuperior bioavailability can be attained). By employing this technologyit is possible to obtain a particulate material that is suitable forprocessing into various pharmaceutical dosage forms e.g. in the form ofpellets or tablets. Furthermore, the technology is suitable for use asit is possible to obtain a suitable release profile of the activesubstance, e.g. such as those release profiles described herein. In oneembodiment, pellets suitable for use may have a mean particle sizelarger than 2000 μm. In another embodiment, pellets suitable for use mayhave a mean particle size of from about 0.01 μm to about 250 μm.

Another specific suitable formulation principle for use in the presentcontext is formulation in a lipophilic environment such as, e.g., softgelatin capsules. A suitable example of this formulation principle isVegicaps Soft from Scherer (a soft capsule technology based oncarrageenan and starch, which despite being 100% plant-derived, stilloffers all the key attributes of traditional soft gelatin capsules.These include a soft and flexible dosage form that provides ease ofswallowing.) (For further information seehttp://www.rpscherer.de/page.php?pageID=94).

A further specific example of a suitable formulation comprises theformulation of the active substance together with Vitamin E concentratein soft or hard gelatin capsules. This formulation, in a modified form,is the basis of the commercial cyclosporine product, Neoral®,containing, among other things, corn oil-mono-di-triglycerides, polyoxyl40 hydrogenated castor oil NF, DL-α-tocopherol USP (part of the vitaminE family), gelatin NF, glycerol, iron oxide black, propylene glycol USP,titanium dioxide USP, carmine, and alcohol in addition to cyclosporine.

Another specific example of a suitable formulation comprises theformulation of active substance together with ethanol,tocopherolethylene glycol 1000 succinate (TPGS), corn oil and wax insoft or hard gelatin capsules. This product can be a semi-solid or soliddosage form. The release rate of this formulation is dependent ondegradation due to lipases in the intestine.

A further example of a suitable formulation comprises the formulation ofthe active substance together with ethanol, tocopherolethylene glycol1000 succinate (TPGS), corn oil and polyglycolized glycerides (e.g.Gelucire) in soft or hard gelatin capsules. This product can be asemi-solid or solid dosage form. The release rate of this formulation isdependent on degradation due to lipases in the intestine.

A further example of a suitable formulation is an oral pulsed dose drugdelivery system. This dosage form can be perceived as a modified form ofthe Schering Repetab tablets. A portion of the composition of thepresent invention is put in the core of a tablet.

The core can for example be made by conventional wet granulation orcontinuous granulation such as extrusion followed by compaction of thegranulate into tablets. The core is then coated using an appropriatetechnology, preferably by airsuspension using an enteric coating polymersuch as Eudragits.

The first releasing dose is compression coated on the core orair-suspension coated either with the enteric coat or on top of theenteric coat. In a embodiment of the invention, the first releasing doseis air-suspension coated with the enteric coat. In a further embodimentof the invention, the first releasing dose is compression coated on thecore, in order to avoid release of the composition according to theinvention prior to the degradation of the enteric coat, such degradationtypically occurring at pH values higher than those found in the gastricventricle; i.e. the degradation of the enteric coat typically occursafter passage of the gastric ventricle.

A further example of a suitable formulation is an oral sustained drugdelivery system. A portion of the composition of the present inventionis put in the core of a tablet.

The core can for example be made by conventional wet granulation orcontinuous granulation such as extrusion followed by compaction of thegranulate into tablets. The core is coated using an appropriatetechnology, preferably by airsuspension using ethylcellulose and ahydrophilic excipient such as hydroxyl propyl cellulose (HPC).

The first releasing dose is compression coated on the core orair-suspension coated either with the enteric coat or on top of theenteric coat. In a preferred embodiment of the invention, the firstreleasing dose is air-suspension coated with the enteric coat. In afurther embodiment of the invention, the first releasing dose iscompression coated on the core, in order to avoid release of thecomposition according to the invention prior to the degradation of theenteric coat, such degradation typically occurring at pH values higherthan those found in the gastric ventricle; i.e. the degradation of theenteric coat typically occurs after passage of the gastric ventricle.

A further example of a suitable formulation is obtained via crystalengineering, such as e.g. described in WO 03/080034, which is herebyincorporated by reference.

Accordingly, in another embodiment the composition of the inventioncomprises the active substance in the form of micro-crystals withhydrophilic surfaces. Furthermore, in another embodiment of theinvention, the micro-crystals are filmcoated directly, in order toachieve a sustained release formulation.

Another specific example of a suitable formulation comprisescomplexation of the composition according to the present invention withgenuine cyclodextrins and cyclodextrin-derivatives (e.g. alkyl- andhydroxyalkyl-derivatives or sulfobutyl-derivatives). The complexation isachieved in accordance with well known methods. It is contemplated thatsuch a complexation leads to a higher solubility and a higherdissolution rate of the composition according to the invention, comparedto the composition prior to complexation. Furthermore, it iscontemplated that such a complexation leads to a higher bioavailabilityof the composition according to the invention, compared to thecomposition prior to complexation.

In specific embodiments, the invention relates to a controlled releasepharmaceutical composition that may be administered one, two or moretimes daily, such as once or twice or three times daily. Furthermore,the composition may be designed so that it releases the fumaric acidester relatively independent on pH, i.e. the release is not dependent onpH in the gastrointestinal tract. Examples of such compositions are e.g.compositions in the form of solid dosages forms (e.g. tablets, capsules,pellets, beads etc.) that are coated with a controlled release coating.Suitable materials for controlled release coatings are e.g. celluloseand cellulose derivatives including methylcellulose, ethylcellulose andcellulose acetate, or poly(ethylene-co-vinyl acetate), poly (vinylchloride).

The release of the fumaric acid ester typically takes place in threesteps from a composition coated with a diffusion controlled membrane:

i) firstly, water (from the GI tract) diffuses into the dosage form fromthe surroundings,

ii) secondly, at least some of the fumaric acid ester present in thedosage form dissolves by the action of water,

iii) the dissolved fumaric acid ester diffuses out of the dosage formand into the surroundings (i.e. the GI tract)

Other examples include e.g. matrix tablets or dosage form containing amultiplicity of units each in the form of a matrix system. The activesubstance is embedded in a matrix containing e.g. cellulose andcellulose derivatives including microcrystalline cellulose,hydroxypropyl methyl cellulose, hydroxypropyl cellulose andmethylcellulose, povidone, poly(ethyleneoxide) (PEO), polyethyleneglycol (PEG), poly (vinyl alcohol) (PVA), xanthan gum, carrageenan andother synthetic materials. Substances normally used as pharmaceuticallyacceptable excipients or additives may be added to a matrix composition.

Other examples of suitable compositions are e.g. hydrogels, i.e.monolithic systems wherein the active substance is embedded in awater-swellable network polymer. Materials suitable for use include e.g.hydrophilic vinyl and acrylic polymers, polysaccharides like alginates,and poly(ethylene oxide).

In specific embodiments, a composition according to the invention has apH controlled release (also known as a pH dependent release) of thefumaric acid ester. Normally, the release is designed so that only asmall amount, if any, of the fumaric acid ester is released in thestomach (pH up to about 3), whereas the fumaric acid ester is releasedin the intestines (pH shifts to about 6-7). Such a pH controlled releasecan be obtained by providing a composition of the invention with anenteric coating (the whole composition or, if the composition is amultiparticulate composition, the individual units) or by providing acomposition that releases the fumaric acid by a pH-dependent osmoticmechanism, or by employment of suitable enzymes.

Examples of suitable substances for use as enteric coating materialsinclude polyacrylamides, phthalate derivatives such as acid phthalatesof carbohydrates, amylose acetate phthalate, cellulose acetatephthalate, other cellulose ester phthalates, cellulose ether phthalates,hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate,hydroxypropylmethylcellulose phthalate, methylcellulose phthalate,polyvinyl acetate phthalate, poly acrylic methacrylic acid copolymers,shellac and vinyl acetate and crotonic acid copolymers, etc.

The compositions mentioned above having a pH independent release mayalso be formulated to release the fumaric acid ester e.g. by providingthe composition with an outer layer of an enteric coating.

Furthermore, the compositions may be formulated in such a manner that aninitial delay in release of the fumaric acid ester is obtained. Such adelay may be obtained e.g. by choosing an outermost coating that in atime-controlled manner degrades (e.g. erodes) and only when thisoutermost coating is eroded away, the release of the fumaric acid esterstarts.

In the following is given a description of various compositionsaccording to the invention that are designed to obtain a suitablerelease of the fumaric acid ester. Based on the description above andhandbooks within the field of controlled release of pharmaceutics, aperson skilled in the art will know how to choose different formulationprinciples in order to achieve the required release profile.

Compositions Designed to be Administered Two or More Times Daily

pH Independent Release

In the following is given a description of specific embodiments, whereinthe fumaric acid ester is released independently of pH and wherein therelease pattern is suitable for compositions that are administered twoor more times daily. Examples of suitable formulation principles aree.g. compositions provided with a diffusion coating such as a controlledrelease diffusion coating, matrix particulates or matrix tablets,hydrogels, pulsed dose drug delivery systems, co-formulation withvitamin E concentrate or ethanol, TPGS, corn oil and wax etc., includingany of the formulation principles mentioned above.

Accordingly, in one aspect the invention relates to a controlled releasepharmaceutical composition for oral use comprising as an activesubstance one or more fumaric acid esters selected fromdi-(C₁-C₅)alkylesters of fumaric acid and mono-(C₁-C₅)alkylesters offumaric acid, or a pharmaceutically acceptable salt thereof, wherein therelease of the fumaric acid ester—when subjected to an in vitrodissolution test employing water as dissolution medium—is as follows:

within the first 6 hours after start of the test at the most about 60%w/w such as, e.g., from about 30% to about 60% w/w, from about 40% toabout 55% w/w, or about 50% of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 9 hours after start of the test at the most about 85%w/w such as, e.g., from about 50% to about 85% w/w, from about 60% toabout 80% w/w, or about 75% of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 12 hours after start of the test at least about 80% w/wsuch as, e.g., about 80% w/w or more, about 85% w/w or more, about 90%w/w or more or about 95% w/w or more of the total amount of the fumaricacid ester contained in the composition is released, and/or

the total amount of the fumaric acid ester contained in the compositionis released within the first 12 hours after start of the test.

pH Controlled Release

In the following is given a description of specific embodiments, whereinthe fumaric acid ester is released depending on pH and wherein therelease pattern is suitable for compositions that are administered twoor more times daily. Examples of suitable formulation principles aree.g. compositions provided with an enteric coating or hydrogels of atype described by Zentner et al (U.S. Pat. No. 6,537,584) and Bae (U.S.Pat. No. 5,484,610), which hereby are incorporated by reference. Furtherexamples of suitable formulation principles are e.g. compositionsprovided with a diffusion coating such as a controlled release diffusioncoating, matrix particulates or matrix tablets, hydrogels, pulsed dosedrug delivery systems, co-formulation with vitamin E concentrate orethanol, TPGS, corn oil and wax etc., including any of the formulationprinciples mentioned above, optionally with an enteric coating.

Accordingly, in one aspect the invention relates to a controlled releasepharmaceutical composition for oral use comprising as an activesubstance one or more fumaric acid esters selected fromdi-(C₁-C₅)alkylesters of fumaric acid and mono-(C₁-C₅)alkylesters offumaric acid, or a pharmaceutically acceptable salt thereof, wherein therelease of the fumaric acid ester—when subjected to an in vitrodissolution test employing 0.1 N hydrochloric acid as dissolution mediumduring the first 2 hours of the test and then 0.05 M phosphate buffer pH6.5 or 6.8 as dissolution medium—is as follows:

within the first 2 hours after start of the test at least about 1% w/wsuch as, e.g. at least about 2% w/w, at least about 3% w/w, or about 5%w/w of the total amount of the fumaric acid ester is released, and/or

within the first 3 hours after start of the test at the most about 35%w/w such as, e.g., from about 15% to about 35% w/w, from about 20% toabout 30% w/w, or about 25% w/w of the total amount of the fumaric acidester is released, and/or

within the first 3 hours after start of the test from about 10% to about70% w/w, from about 10% to about 65% w/w, from about 10% to about 60%w/w, from about 15% to about 50% w/w, from about 15% to about 35% w/w,from about 20% to about 30% w/w, or about 20% w/w, or about 25% w/w ofthe total amount of the fumaric acid ester is released, and/or

within the first 4 hours after start of the test at the most about 92%w/w such as, e.g., from about 10% to about 92% w/w, from about 20% toabout 85% w/w, from about 20% to about 80% w/w, from about 20% to about70% w/w, from about 25% to about 60% w/w, from about 25% to about 55%w/w, from about 30% to about 50% w/w, or about 35% w/w, or about 40%w/w, or about 45% w/w of the total amount of the fumaric acid ester isreleased, and/or

within the first 5 hours after start of the test at the most about 94%w/w such as, e.g., from about 15% to about 94% w/w, from about 25% toabout 90% w/w, from about 30% to about 85% w/w, from about 35% to about80% w/w, from about 35% to about 75% w/w, from about 40% to about 70%w/w, from about 45% to about 70% w/w, from about 55% to about 70% w/w,from about 60% to about 70% w/w, or about 45% w/w, or about 50% w/w, orabout 55% w/w, or about 60% w/w, or about 65% w/w of the total amount ofthe fumaric acid ester is released, and/or

within the first 6 hours after start of the test at the most about 60%w/w such as, e.g., from about 30% to about 60% w/w, from about 40% toabout 55% w/w, or about 50% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 6 hours after start of the test at the most about 95%w/w such as, e.g., from about 35% to about 95% w/w, from about 40% toabout 90% w/w, from about 45% to about 85% w/w, from about 50% to about85% w/w, from about 55% to about 85% w/w, from about 60% to about 85%w/w, from about 65% to about 85% w/w, from about 70% to about 85% w/w,from about 75% to about 85% w/w, or about 65% w/w, or about 70% w/w, orabout 75% w/w, or about 80% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 7 hours after start of the test at the most about 98%w/w such as, e.g., from about 45% to about 98% w/w, from about 50% toabout 98% w/w, from about 55% to about 98% w/w, from about 60% to about98% w/w, from about 65% to about 98% w/w, from about 70% to about 98%w/w, from about 75% to about 95% w/w, from about 80% to about 95% w/w,from about 85% to about 95% w/w, or about 75% w/w, or about 80% w/w, orabout 85% w/w, or about 90% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 9 hours after start of the test at the most about 85%w/w such as, e.g., from about 50% to about 85% w/w, from about 60% toabout 80% w/w, or about 75% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 9 hours after start of the test at the most about 99%w/w such as, e.g., from about 60% to about 99% w/w, from about 70% toabout 99% w/w, from about 80% to about 99% w/w, from about 90% to about99% w/w, or about 95% w/w of the total amount of the fumaric acid estercontained in the composition is released.

In another aspect of the invention a controlled release pharmaceuticalcomposition for oral use comprising as an active substance one or morefumaric acid esters selected from di-(C₁-C₅)alkylesters of fumaric acidand mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceuticallyacceptable salt thereof, characterized in that it consists of acontrolled-release dosage form adapted to release di-(C₁-C₅)alkylesterand/or a mono-(C₁-C₅)alkylester of fumaric acid or a pharmaceuticallyacceptable salt thereof over a predetermined time period, according to ain vitro profile of dissolution when measured according to USP in 0.1 Nhydrochloric acid during the first 2 hours and then 0.05 M phosphatebuffer at a pH 6.5 or 6.8,

wherein at the most 5% w/w of the total amount of the fumaric acid estercontained in the composition is released within the first 2 hours afterstart of the test, and/or

wherein from about 20% to about 75% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 3 hours after start of the test, and/or

wherein from about 50% to about 90% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 4 hours after start of the test, and/or

wherein from about 60% to about 90% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 5 hours after start of the test, and/or

wherein from about 70% to about 95% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 6 hours after start of the test, and/or

wherein from about 75% to about 97% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 7 hours after start of the test, is provided.

In a further aspect of the invention a controlled release pharmaceuticalcomposition for oral use comprising as an active substance one or morefumaric acid esters selected from di-(C₁-C₅)alkylesters of fumaric acidand mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceuticallyacceptable salt thereof, characterized in that it consists of acontrolled-release dosage form adapted to release di-(C₁-C₅)alkylesterand/or a mono-(C₁-C₅)alkylester of fumaric acid or a pharmaceuticallyacceptable salt thereof over a predetermined time period, according to ain vitro profile of dissolution when measured according to USP in 0.1 Nhydrochloric acid during the first 2 hours and then 0.05 M phosphatebuffer at a pH 6.5 or 6.8, wherein at the most 5 w/w of the total amountof the fumaric acid ester contained in the composition is releasedwithin the first 2 hours after start of the test, wherein from about 20%to about 75% w/w of the total amount of the fumaric acid ester containedin the composition is released within the first 3 hours after start ofthe test, wherein from about 50% to about 90% w/w of the total amount ofthe fumaric acid ester contained in the composition is released withinthe first 4 hours after start of the test, wherein from about 60% toabout 90% w/w of the total amount of the fumaric acid ester contained inthe composition is released within the first 5 hours after start of thetest, wherein from about 70% to about 95% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 6 hours after start of the test, wherein from about 75% to about97% w/w of the total amount of the fumaric acid ester contained in thecomposition is released within the first 7 hours after start of thetest, and wherein at least 85% w/w of the total amount of the fumaricacid ester contained in the composition is released within the first 8hours after start of the test, is provided.

In another further aspect of the invention a controlled releasepharmaceutical composition comprising as an active substance one or morefumaric acid esters selected from di-(C₁-C₅)alkylesters of fumaric acidand mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceuticallyacceptable salt thereof, characterized in that it consists of acontrolled-release dosage form adapted to release di-(C₁-C₅)alkylesterand/or a mono-(C₁-C₅)alkylester of fumaric acid or a pharmaceuticallyacceptable salt thereof over a predetermined time period, according to ain vitro profile of dissolution when measured according to USP in 0.1 Nhydrochloric acid during the first 2 hours and then 0.05 M phosphatebuffer at a pH 6.5 or 6.8,

wherein at the most 5% w/w of the total amount of the fumaric acid estercontained in the composition is released within the first 2 hours afterstart of the test and/or,

wherein from about 20% to about 50% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 3 hours after start of the test, and/or

wherein from about 45% to about 70% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 4 hours after start of the test, and/or

wherein from about 65% to about 85% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 5 hours after start of the test, and/or

wherein from about 75% to about 90% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 6 hours after start of the test, is provided.

In yet another aspect of the invention a controlled releasepharmaceutical composition comprising as an active substance one or morefumaric acid esters selected from di-(C₁-C₅)alkylesters of fumaric acidand mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceuticallyacceptable salt thereof, characterized in that it consists of acontrolled-release dosage form adapted to release di-(C₁-C₅)alkylesterand/or a mono-(C₁-C₅)alkylester of fumaric acid or a pharmaceuticallyacceptable salt thereof over a predetermined time period, according to ain vitro profile of dissolution when measured according to USP in 0.1 Nhydrochloric acid during the first 2 hours and then 0.05 M phosphatebuffer at a pH 6.5 or 6.8, wherein at the most 5% w/w of the totalamount of the fumaric acid ester contained in the composition isreleased within the first 2 hours after start of the test, wherein fromabout 20% to about 50% w/w of the total amount of the fumaric acid estercontained in the composition is released within the first 3 hours afterstart of the test, wherein from about 45% to about 70% w/w of the totalamount of the fumaric acid ester contained in the composition isreleased within the first 4 hours after start of the test, wherein fromabout 65% to about 85% w/w of the total amount of the fumaric acid estercontained in the composition is released within the first 5 hours afterstart of the test, wherein from about 75% to about 90% w/w of the totalamount of the fumaric acid ester contained in the composition isreleased within the first 6 hours after start of the test, and whereinat least 80% of the total amount of the fumaric acid ester contained inthe composition is released within the first 7 hours after start of thetest, is provided.

In yet another aspect of the invention a controlled releasepharmaceutical composition comprising as an active substance one or morefumaric acid esters selected from di-(C₁-C₅)alkylesters of fumaric acidand mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceuticallyacceptable salt thereof, characterized in that it consists of acontrolled-release dosage form adapted to release di-(C₁-C₅)alkylesterand/or a mono-(C₁-C₅)alkylester of fumaric acid or a pharmaceuticallyacceptable salt thereof over a predetermined time period, according to ain vitro profile of dissolution when measured according to USP in 0.1 Nhydrochloric acid during the first 2 hours and then 0.05 M phosphatebuffer at a pH 6.5 or 6.8,

wherein at the most 5% w/w of the total amount of the fumaric acid estercontained in the composition is released within the first 2 hours afterstart of the test, and/or

wherein from about 50% to about 75% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 3 hours after start of the test, and/or

wherein from about 70% to about 90% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 4 hours after start of the test, and/or

wherein from about 80% to about 90% w/w of the total amount of thefumaric acid ester contained in the composition is released within thefirst 5 hours after start of the test, is provided.

In yet another aspect of the invention a controlled releasepharmaceutical composition comprising as an active substance one or morefumaric acid esters selected from di-(C₁-C₅)alkylesters of fumaric acidand mono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceuticallyacceptable salt thereof, characterized in that it consists of acontrolled-release dosage form adapted to release di-(C₁-C₅)alkylesterand/or a mono-(C₁-C₅)alkylester of fumaric acid or a pharmaceuticallyacceptable salt thereof over a predetermined time period, according to ain vitro profile of dissolution when measured according to USP in 0.1 Nhydrochloric acid during the first 2 hours and then 0.05 M phosphatebuffer at a pH 6.5 or 6.8, wherein at the most 5% w/w of the totalamount of the fumaric acid ester contained in the composition isreleased within the first 2 hours after start of the test, wherein fromabout 50% to about 75% w/w of the total amount of the fumaric acid estercontained in the composition is released within the first 3 hours afterstart of the test, wherein from about 70% to about 90% w/w of the totalamount of the fumaric acid ester contained in the composition isreleased within the first 4 hours after start of the test, wherein fromabout 80% to about 90% w/w of the total amount of the fumaric acid estercontained in the composition is released within the first 5 hours afterstart of the test and wherein from about at least 90% w/w of the totalamount of the fumaric acid ester contained in the composition isreleased within the first 6 hours after start of the test, is provided.

Release Over Gradually Shifting pH (“Half-Change” Method)

In the following is given a description of specific embodiments, whereinthe fumaric acid ester is released depending on pH and wherein therelease pattern is suitable for compositions that are administered twoor more times daily. Examples of suitable formulation principles aree.g. compositions provided with an enteric coating or hydrogels of atype described by Zentner et al (U.S. Pat. No. 6,537,584) and Bae (U.S.Pat. No. 5,484,610), which hereby are incorporated by reference. Furtherexamples of suitable formulation principles are e.g. compositionsprovided with a diffusion coating such as a controlled release diffusioncoating, matrix particulates or matrix tablets, hydrogels, pulsed dosedrug delivery systems, co-formulation with vitamin E concentrate orethanol, TPGS, corn oil and wax etc., including any of the formulationprinciples mentioned above, optionally with an enteric coating.

The “half-change” method has specifically been developed forenteric-coated or sustained release preparations. This methodencompasses hourly replacing half of the dissolution medium by analiquot of neutral dissolution medium (to simulate the GI passage withrespect to the slightly shifting pH values from duodenum to ileum). Theapproach is described in the following table:

Ratio of simulated Time from start gastric fluid/simulated (hours)intestinal fluid (%) pH value 0-1 100/0  1.3 1-2 50/50 2.4 2-3 25/75 6.23-4 12.5/87.5 6.8 4-5  6.25/93.75 7.1 5-6 ~3/97 7.2 6-7 ~1/99 7.3 7-8 ~0/100 7.3

The composition of the simulated gastric fluid can e.g. be found in theUnited States Pharmacopeia (USP) 2005:

2.0 g of NaCl and 3.2 g of purified pepsin, derived from porcine gastricmucosa, with an activity of 800 to 2500 units per mg of protein, isdissolved in 7.0 mL of hydrochloric acid and sufficient water to make1000 mL. The resulting test solution has a pH of about 1.2.

Another composition of the simulated gastric fluid is found in theGerman E DIN 19738 (Deutsche Industrie Norm):

100 mL of synthetic/simulated gastric fluid contains 290 mg of NaCl, 70mg of KCl, 27 mg of KH₂PO₄ and enough HCl to adjust the pH to 2.0. Inaddition, it contains 100 mg pepsin and 300 mg of mucin.

The composition of the simulated intestinal fluid can e.g. be found inthe United States Pharmacopeia (USP) 2005:

6.8 g of monobasic potassium phosphate is dissolved in 250 mL of water.Mix and add 77 mL of 0.2 N sodium hydroxide and 500 mL of water. 10.0 gof pancreatin is added, the solution is mixed and adjusted to a pH of6.8±0.1 by adding either 0.2 N sodium hydroxide or 0.2 N hydrochloricacid. The resulting solution is diluted with water to 1000 mL.

Another composition of the simulated intestinal fluid is found in theGerman E DIN 19738 (Deutsche Industrie Norm):

100 mL of synthetic/simulated intestinal fluid contains 30 mg of KCl, 50mg of CaCl₂, 20 mg of MgCl₂ and sufficient NaHCO₃ to adjust the pH to7.5. Furthermore, it contains 30 mg of trypsin, 900 mg of pancreatin,900 mg of lyophilized bile and 30 mg of urea.

In a preferred embodiment of the present invention, the “half-change”method is carried out with the simulated gastric fluid and the simulatedintestinal fluid as defined by the USP 2005.

In another embodiment of the present invention, the “half-change” methodis carried out with the simulated gastric fluid and the simulatedintestinal fluid as defined by the USP 2005, but without the proteins(i.e. without the pepsin in the simulated gastric fluid, and without thepancreatin in the simulated intestinal fluid).

Accordingly, in one aspect the invention relates to a controlled releasepharmaceutical composition for oral use comprising as an activesubstance one or more fumaric acid esters selected fromdi-(C₁-C₅)alkylesters of fumaric acid and mono-(C₁-C₅)alkylesters offumaric acid, or a pharmaceutically acceptable salt thereof, wherein therelease of the fumaric acid ester—when subjected to an in vitrodissolution test according to the “half-change” method—is as follows:

within the first 3 hours after start of the test from about 20% to about40% w/w, from about 20% to about 35% w/w, or about 30% w/w of the totalamount of the fumaric acid ester is released, and/or

within the first 3 hours after start of the test at least about 12% w/wsuch as, e.g., from about 12% to about 50% w/w, from about 15% to about45% w/w, from about 20% to about 40% w/w, from about 20% to about 35%w/w, from about 22% to about 35% w/w, or about 25% w/w, or about 30% w/wof the total amount of the fumaric acid ester is released, and/or

within the first 4 hours after start of the test from about 25% to about40% w/w, from about 30% to about 40% w/w, or about 40% w/w of the totalamount of the fumaric acid ester is released, and/or

within the first 4 hours after start of the test at least about 76% w/wsuch as, e.g., from about 76% to about 95% w/w, from about 80% to about90% w/w, or about 80% w/w, or about 85% w/w of the total amount of thefumaric acid ester is released, and/or

within the first 4 hours after start of the test at the most about 40%w/w such as, e.g., from about 10% to about 40% w/w, from about 15% toabout 35% w/w, from about 20% to about 30% w/w, or about 25% w/w, orabout 30% w/w of the total amount of the fumaric acid ester is released,and/or

within the first 6 hours after start of the test at least about 81% w/wsuch as, e.g., from about 81% to about 96% w/w, from about 85% to about95% w/w, from about 85% to about 90% w/w, or about 80% w/w, or about 85%w/w, or about 90% w/w of the total amount of the fumaric acid estercontained in the composition is released, and/or

within the first 6 hours after start of the test at the most about 50%w/w such as, e.g., from about 20% to about 50% w/w, from about 25% toabout 45% w/w, from about 30% to about 45% w/w, or about 40% w/w, orabout 45% w/w of the total amount of the fumaric acid ester contained inthe composition is released, and/or

within the first 7 hours after start of the test at least about 82% w/wsuch as, e.g., from about 82% to about 99% w/w, from about 85% to about99% w/w, from about 85% to about 95% w/w, or about 90% w/w of the totalamount of the fumaric acid ester contained in the composition isreleased, and/or

within the first 7 hours after start of the test at the most about 65%w/w such as, e.g., from about 25% to about 65% w/w, from about 30% toabout 65% w/w, from about 35% to about 60% w/w, from about 40% to about60% w/w, from about 50% to about 60% w/w, or about 55% w/w, or about 60%w/w of the total amount of the fumaric acid ester contained in thecomposition is released, and/or

within the first 8 hours after start of the test at the most about 85%w/w such as, e.g., from about 50% to about 85% w/w, from about 60% toabout 80% w/w, or about 75% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 8 hours after start of the test at the most about 92%w/w such as, e.g., from about 30% to about 92% w/w, from about 35% toabout 90% w/w, from about 40% to about 85% w/w, from about 45% to about80% w/w, from about 50% to about 75% w/w, from about 55% to about 75%w/w, from about 60% to about 75% w/w, or about 65% w/w, or about 70% w/wof the total amount of the fumaric acid ester contained in thecomposition is released, and/or

within the first 12 hours after start of the test at least about 80% w/wsuch as, e.g., about 80% w/w or more, about 85% w/w or more, about 90%w/w or more or about 95% w/w or more of the total amount of the fumaricacid ester contained in the composition is released.

Slow Release

In the following is given a description of specific embodiments, whereinthe fumaric acid ester is released in a slow or delayed manner whereinthe release pattern is suitable for compositions that are administeredtwo or more times daily. Examples of suitable formulation principles areany of those described above.

Accordingly, in one aspect the invention relates to a controlled releasepharmaceutical composition for oral use comprising as an activesubstance one or more fumaric acid esters selected fromdi-(C₁-C₅)alkylesters of fumaric acid and mono-(C₁-C₅)alkylesters offumaric acid, or a pharmaceutically acceptable salt thereof, wherein therelease of the fumaric acid ester—when subjected to an in vitrodissolution test employing water as dissolution medium—is as follows:

within the first 6 hours after start of the test at the most about 35%w/w such as, e.g., from about 15% to about 35% w/w such as, e.g., fromabout 20% to about 30% w/w, or about 25% w/w of the total amount of thefumaric acid ester contained in the composition is released, and/or

within the first 8 hours after start of the test at the most about 60%w/w such as, e.g., from about 30% to about 60% w/w such as, e.g., fromabout 40% to about 55% w/w, or about 50% w/w of the total amount of thefumaric acid ester contained in the composition is released, and/or

within the first 10 hours after start of the test at the most about 85%w/w such as, e.g., from about 50% to about 85% w/w such as, e.g., fromabout 60% to about 80% w/w, or about 75% w/w of the total amount of thefumaric acid ester contained in the composition is released, and/or

within the first 12 hours after start of the test at least about 80% w/wsuch as, e.g., about 80% w/w or more such as, e.g., about 85% w/w ormore, about 90% w/w or more or about 95% w/w or more of the total amountof the fumaric acid ester contained in the composition is released.

Compositions Designed to be Administered Once Daily

pH Independent Release

In the following is given a description of specific embodiments, whereinthe fumaric acid ester is released independent of pH and wherein therelease pattern is suitable for compositions that are administered oncedaily. Examples of suitable formulation principles are e.g. compositionsprovided with a diffusion coating such as a controlled release diffusioncoating, matrix particulates or matrix tablets, hydrogels, pulsed dosedrug delivery systems, co-formulation with vitamin E concentrate orethanol, TPGS, corn oil and wax etc., including any of the formulationprinciples mentioned above.

Accordingly, in one aspect the invention relates to a controlled releasepharmaceutical composition for oral use comprising as an activesubstance one or more fumaric acid esters selected fromdi-(C₁-C₅)alkylesters of fumaric acid and mono-(C₁-C₅)alkylesters offumaric acid, or a pharmaceutically acceptable salt thereof, wherein therelease of the fumaric acid ester—when subjected to an in vitrodissolution test employing water as dissolution medium—is as follows:

within the first 9 hours after start of the test at the most about 60%w/w such as, e.g., from about 30% to about 60% w/w, from about 40% toabout 55% w/w, or about 50% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 13.5 hours after start of the test at the most about85% w/w such as, e.g., from about 50% to about 85% w/w, from about 60%to about 80% w/w, or about 75% w/w of the total amount of the fumaricacid ester contained in the composition is released, and/or

within the first 18 hours after start of the test at least about 80% w/wsuch as, e.g., about 80% w/w or more, about 85% w/w or more, about 90%w/w or more or about 95% w/w or more of the total amount of the fumaricacid ester contained in the composition is released, and/or

the total amount of the fumaric acid ester contained in the compositionis released within the first 18 hours after start of the test.

pH Controlled Release

In the following is given a description of specific embodiments, whereinthe fumaric acid ester is released dependently of pH and wherein therelease pattern is suitable for compositions that are administered oncedaily. Examples of suitable formulation principles are e.g. compositionsprovided with an enteric coating or hydrogels of a type described byZentner et al (U.S. Pat. No. 6,537,584) and Bae (U.S. Pat. No.5,484,610). Further examples of suitable formulation principles are e.g.compositions provided with a diffusion coating such as a controlledrelease diffusion coating, matrix particulates or matrix tablets,hydrogels, pulsed dose drug delivery systems, co-formulation withvitamin E concentrate or ethanol, TPGS, corn oil and wax etc., includingany of the formulation principles mentioned above, optionally with anenteric coating.

Accordingly, in one aspect the invention relates to a controlled releasepharmaceutical composition for oral use comprising as an activesubstance one or more fumaric acid esters selected fromdi-(C₁-C₅)alkylesters of fumaric acid and mono-(C₁-C₅)alkylesters offumaric acid, or a pharmaceutically acceptable salt thereof, wherein therelease of the fumaric acid ester—when subjected to an in vitrodissolution test employing 0.1 N hydrochloric acid as dissolution mediumduring the first 2 hours of the test and then 0.05 M phosphate buffer pH6.5 or 6.8 as dissolution medium—is as follows:

within the first 2 hours after start of the test at least about 1% w/wsuch as, e.g. at least about 2% w/w, at least about 3% w/w, or about 5%w/w of the total amount of the fumaric acid ester is released, and/or

within the first 4 hours after start of the test at the most about 90%w/w such as, e.g., from about 5% to about 90% w/w, from about 5% toabout 85% w/w, from about 10% to about 80% w/w, from about 10% to about70% w/w, from about 10% to about 65% w/w, from about 10% to about 60%w/w, from about 15% to about 50% w/w, from about 15% to about 35% w/w,from about 20% to about 30% w/w, or about 20% w/w, or about 25% w/w ofthe total amount of the fumaric acid ester is released, and/or

within the first 4.5 hours after start of the test at the most about 35%w/w such as, e.g., from about 15% to about 35% w/w, from about 20% toabout 30% w/w, or about 25% w/w of the total amount of the fumaric acidester is released, and/or

within the first 5 hours after start of the test at the most about 92%w/w such as, e.g., from about 10% to about 92% w/w, from about 20% toabout 85% w/w, from about 20% to about 80% w/w, from about 20% to about70% w/w, from about 25% to about 60% w/w, from about 25% to about 55%w/w, from about 30% to about 50% w/w, or about 35% w/w, or about 40%w/w, or about 45% w/w of the total amount of the fumaric acid ester isreleased, and/or

within the first 6 hours after start of the test at the most about 94%w/w such as, e.g., from about 15% to about 94% w/w, from about 25% toabout 90% w/w, from about 30% to about 85% w/w, from about 35% to about80% w/w, from about 35% to about 75% w/w, from about 40% to about 70%w/w, from about 45% to about 70% w/w, from about 55% to about 70% w/w,from about 60% to about 70% w/w, or about 45% w/w, or about 50% w/w, orabout 55% w/w, or about 60% w/w, or about 65% w/w of the total amount ofthe fumaric acid ester is released, and/or

within the first 7 hours after start of the test at the most about 95%w/w such as, e.g., from about 35% to about 95% w/w, from about 40% toabout 90% w/w, from about 45% to about 85% w/w, from about 50% to about85% w/w, from about 55% to about 85% w/w, from about 60% to about 85%w/w, from about 65% to about 85% w/w, from about 70% to about 85% w/w,from about 75% to about 85% w/w, or about 65% w/w, or about 70% w/w, orabout 75% w/w, or about 80% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 9 hours after start of the test at the most about 98%w/w such as, e.g., from about 45% to about 98% w/w, from about 50% toabout 98% w/w, from about 55% to about 98% w/w, from about 60% to about98% w/w, from about 65% to about 98% w/w, from about 70% to about 98%w/w, from about 75% to about 95% w/w, from about 80% to about 95% w/w,from about 85% to about 95% w/w, or about 75% w/w, or about 80% w/w, orabout 85% w/w, or about 90% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 9 hours after start of the test at the most about 60%w/w such as, e.g., from about 30% to about 60% w/w, from about 40% toabout 55% w/w, or about 50% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 12 hours after start of the test at the most about 99%w/w such as, e.g., from about 60% to about 99% w/w, from about 70% toabout 99% w/w, from about 80% to about 99% w/w, from about 90% to about99% w/w, or about 95% w/w of the total amount of the fumaric acid estercontained in the composition is released, and/or

within the first 13.5 hours after start of the test at the most about85% w/w such as, e.g., from about 50% to about 85% w/w, from about 60%to about 80% w/w, or about 75% w/w of the total amount of the fumaricacid ester contained in the composition is released.

Release Over Gradually Shifting pH (“Half-Change” Method)

In the following is given a description of specific embodiments, whereinthe fumaric acid ester is released depending on pH and wherein therelease pattern is suitable for compositions that are administered oncedaily. Examples of suitable formulation principles are e.g. compositionsprovided with an enteric coating or hydrogels of a type described byZentner et al (U.S. Pat. No. 6,537,584) and Bae (U.S. Pat. No.5,484,610), which hereby are incorporated by reference. Further examplesof suitable formulation principles are e.g. compositions provided with adiffusion coating such as a controlled release diffusion coating, matrixparticulates or matrix tablets, hydrogels, pulsed dose drug deliverysystems, co-formulation with vitamin E concentrate or ethanol, TPGS,corn oil and wax etc., including any of the formulation principlesmentioned above, optionally with an enteric coating.

Accordingly, in one aspect the invention relates to a controlled releasepharmaceutical composition for oral use comprising as an activesubstance one or more fumaric acid esters selected fromdi-(C₁-C₅)alkylesters of fumaric acid and mono-(C₁-C₅)alkylesters offumaric acid, or a pharmaceutically acceptable salt thereof, wherein therelease of the fumaric acid ester—when subjected to an in vitrodissolution test according to the “half-change” method—is as follows:

within the first 3 hours after start of the test at least about 12% w/wsuch as, e.g., from about 12% to about 60% w/w, from about 15% to about50% w/w, from about 20% to about 40% w/w, from about 20% to about 35%w/w, or about 25% w/w, or about 30% w/w of the total amount of thefumaric acid ester is released, and/or

within the first 4 hours after start of the test at the most about 35%w/w such as, e.g., from about 15% to about 35% w/w, from about 20% toabout 30% w/w, or about 25% w/w of the total amount of the fumaric acidester is released, and/or

within the first 5 hours after start of the test at the most about 45%w/w such as, e.g., from about 10% to about 45% w/w, from about 15% toabout 40% w/w, from about 15% to about 35% w/w, from about 20% to about30% w/w, or about 25% w/w, or about 30% w/w of the total amount of thefumaric acid ester is released, and/or

within the first 7 hours after start of the test at the most about 65%w/w such as, e.g., from about 20% to about 65% w/w, from about 20% toabout 60% w/w, from about 20% to about 50% w/w, from about 25% to about45% w/w, from about 30% to about 45% w/w, or about 40% w/w, or about 45%w/w of the total amount of the fumaric acid ester is released, and/or

within the first 8 hours after start of the test at the most about 92%w/w such as, e.g., from about 25% to about 92% w/w, from about 25% toabout 90% w/w, from about 30% to about 80% w/w, from about 35% to about70% w/w, from about 40% to about 65% w/w, from about 45% to about 60%w/w, from about 50% to about 60% w/w, or about 55% w/w, or about 60% w/wof the total amount of the fumaric acid ester contained in thecomposition is released, and/or

within the first 8 hours after start of the test at the most about 60%w/w such as, e.g., from about 30% to about 60% w/w, from about 40% toabout 55% w/w, or about 50% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 12 hours after start of the test at the most about 99%w/w such as, e.g., from about 30% to about 99% w/w, from about 30% toabout 95% w/w, from about 35% to about 90% w/w, from about 40% to about85% w/w, from about 45% to about 80% w/w, from about 50% to about 75%w/w, from about 55% to about 75% w/w, from about 60% to about 75% w/w,or about 65% w/w, or about 70% w/w of the total amount of the fumaricacid ester contained in the composition is released, and/or

within the first 12.5 hours after start of the test at the most about85% w/w such as, e.g., from about 50% to about 85% w/w, from about 60%to about 80% w/w, or about 75% w/w of the total amount of the fumaricacid ester contained in the composition is released, and/or

within the first 18 hours after start of the test at least about 80% w/wsuch as, e.g., about 80% w/w or more, about 85% w/w or more, about 90%w/w or more or about 95% w/w or more of the total amount of the fumaricacid ester contained in the composition is released.

Slow Release

In the following is given a description of specific embodiments, whereinthe fumaric acid ester is released in a slow or delayed manner whereinthe release pattern is suitable for compositions that are administeredonce daily. Examples of suitable formulation principles are any of thosedescribed above.

Accordingly, in one aspect the invention relates to a controlled releasepharmaceutical composition for oral use comprising as an activesubstance one or more fumaric acid esters selected fromdi-(C₁-C₅)alkylesters of fumaric acid and mono-(C₁-C₅)alkylesters offumaric acid, or a pharmaceutically acceptable salt thereof, wherein therelease of the fumaric acid ester—when subjected to an in vitrodissolution test employing water as dissolution medium—is as follows:

within the first 7 hours after start of the test at the most about 35%w/w such as, e.g., from about 15% to about 35% w/w, from about 20% toabout 30% w/w, or about 25% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 11 hours after start of the test at the most about 60%w/w such as, e.g., from about 30% to about 60% w/w, from about 40% toabout 55% w/w, or about 50% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 14 hours after start of the test at the most about 85%w/w such as, e.g., from about 50% to about 85% w/w, from about 60% toabout 80% w/w, or about 75% w/w of the total amount of the fumaric acidester contained in the composition is released, and/or

within the first 18 hours after start of the test at least about 80% w/wsuch as, e.g., about 80% w/w or more, about 85% w/w or more, about 90%w/w or more or about 95% w/w or more of the total amount of the fumaricacid ester contained in the composition is released.

Typically, as described above, the compositions according to theinvention are designed to deliver the active substance (i.e. themonoalkylester of fumaric acid, which in turn is metabolised to fumaricacid and, which subsequently is subjected to a rapid eliminationprocess) in a prolonged manner. Apart from the characteristic in vitrorelease patterns described herein, such a prolonged release is reflectedin the pharmacokinetic parameters obtained after a clinical study aswell. Accordingly, it is contemplated that the C_(max) of themonoalkylester of fumaric acid (which appears in the plasma uponhydrolysis or metabolism of the dialkylester administered) is of thesame order of magnitude as previously described in the literatureprovided that a similar or equivalent dose is administered (i.e. C_(max)of monomethylfumarate in a range of from about 0.4 to about 2.0 mg/lcorresponding to an oral dose of 120 to 240 mg dimethylfumarate).However, in order to avoid many frequent daily administrations (2-4tablets 1-3 times daily) it is an aim to prolong the time period wherethe concentration is within the therapeutic window. Accordingly, it iscontemplated that W₅₀ (i.e. the time period in which the plasmaconcentration is 50% of C_(max) or more) is prolonged compared to themarketed treatment with at least 10% such as, e.g. at least 20%, atleast 30%, at least 40% or at least 50%. A suitable W₅₀ is believed tobe at least 2 hours such as in a range of from about 2 to about 15 hoursor from about 2.5 to about 10 hours or from about 3 to about 8 hours.

Furthermore, it is contemplated that a controlled release compositionaccording to the invention may lead to a reduced interindividual and/orintraindividual variation in the plasma profile and to a reduceddependency on whether the composition is taken together with or withoutfood (a reduced variation of the plasma concentration profile ofmonomethylfumarate when the pharmaceutical composition is administeredwith or without concomitant food intake). Therefore, the controlledrelease composition according to the invention may lead to a reducedfrequency of dosing and/or a reduced average total daily dose, and/or anincreased efficacy at the same total daily dose of the active substancecompared to Fumaderm®.

Different kinetic models, such as zero-order (1), first-order (2),square-root (Higuchi's equation) (3) can be applied to theinterpretation of the drug release kinetic.

M _(t) =M ₀ +k ₀ *t  1:

ln M _(t)=ln M+k ₁ *t  2:

M _(t) =M ₀ +k _(H) *t ^(1/2)  3:

In these equations, M_(t) is the cumulative amount of drug released atany specified time point and M₀ is the dose of active substanceincorporated in the pharmaceutical compostion. k₀, k₁ and k_(H) are rateconstants for zero-order, first-order and Higuchi's equation,respectively.

One aspect of the invention relates to a zero-order dissolution releaseprofile. Another aspect relates to a first-order dissolution releaseprofile. A further aspect relates to a square-root (Higuchi's equation)dissolution release profile.

In one aspect of the invention a controlled release pharmaceuticalcomposition comprising as an active substance from 10% to 90% by weightof one or more fumaric acid esters selected from di-(C₁-C₅)alkylestersof fumaric acid and mono-(C₁-C₅)alkylesters of fumaric acid, or apharmaceutically acceptable salt thereof, from 2% to 40% by weightpharmaceutically acceptable polymer(s), and from 1% to 40% by weighthydrophilic excipient(s), and optionally pharmaceutically acceptableexcipients or additives, is provided.

In another aspect of the invention a controlled release pharmaceuticalcomposition comprising as an active substance from 40% to 60% by weightof one or more fumaric acid esters selected from di-(C₁-C₅)alkylestersof fumaric acid and mono-(C₁-C₅)alkylesters of fumaric acid, or apharmaceutically acceptable salt thereof, from 15% to 25% by weightpharmaceutically acceptable polymer(s), and from 2% to 15% by weighthydrophilic excipient(s), and optionally pharmaceutically acceptableexcipients or additives, is provided.

In a further aspect of the invention a controlled release pharmaceuticalcomposition comprising as an active substance from 65% to 80% by weightof one or more fumaric acid esters selected from di-(C₁-C₅)alkylestersof fumaric acid and mono-(C₁-C₅)alkylesters of fumaric acid, or apharmaceutically acceptable salt thereof, from 10% to 25% by weightpharmaceutically acceptable polymer(s), and from 2% to 15% by weighthydrophilic excipient(s), and optionally pharmaceutically acceptableexcipients or additives, is provided.

Examples of “pharmaceutically acceptable polymer(s)” comprises but arenot limited to ethylcellulose, or methacrylic/acrylic acid copolymers,such as ammonio methacrylate copolymer type A and B or methacrylic acidcopolymer A and B.

Examples of “hydrophilic excipient(s)” comprises but are not limited topolyethylene glycol (PEG), povidone, hydroxyl propyl cellulose (HPC),hydroxyethyl starch (HES) or hydroxypropyl methyl cellulose (HPMC) or amaterial with similar properties, or a combination thereof.

In a further aspect of the invention a controlled release pharmaceuticalcomposition, wherein the pharmaceutically acceptable polymer is ethylcellulose, is provided.

In another aspect of the invention a controlled release pharmaceuticalcomposition, wherein the hydrophilic excipient is hydroxyl propylcellulose, is provided.

In another aspect of the invention a controlled release pharmaceuticalcomposition, wherein the hydrophilic excipient is polyethylene glycol,is provided.

In yet another aspect of the invention a controlled releasepharmaceutical composition comprising as an active substance as anactive substance from 10% to 90% by weight of one or more fumaric acidesters selected from di-(C₁-C₅)alkylesters of fumaric acid andmono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceuticallyacceptable salt thereof, and 2% to 40% by weight methacrylic acidcopolymer A and B in a weight ratio between 1:9 and 9:1, and optionallypharmaceutically acceptable excipients or additives, is provided.

In a further aspect of the invention a controlled release pharmaceuticalcomposition comprising from 50% to 90% of one or more fumaric acidesters selected from di-(C₁-C₅)alkylesters of fumaric acid andmono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceuticallyacceptable salt thereof, is provided.

Various controlled release formulations, not limiting the scope of thepresent invention, illustrating the invention are described hereafter(all concentrations based on the final tablet):

1) Granules

Granules may be prepared by mixing and/or granulating the activesubstance at a concentration of about 10 to about 90%, especially fromabout 50 to about 70%, with granulating excipients, such aspharmaceutical acceptable polymers, e.g. ethylcellulose such as Ethocel®NF premium, or methacrylic/acrylic acid copolymers, such as ammoniomethacrylate copolymer type A and B (in a weight ratio of 1:9 to 9:1) ormethacrylic acid copolymer A and B (in a weight ratio of 1:9 to 9:1),incorporated at a concentration between about 2 to about 40%.Hydrophilic excipients such as polyethylene glycol (PEG), povidone,hydroxyl propyl cellulose (HPC), hydroxyethyl starch (HES) orhydroxypropyl methyl cellulose (HPMC) at a concentration of about 1 toabout 40% and/or pharmaceutical acceptable surfactants with HLB valuesabove 8 at a concentration of about 0.01 to about 3% may beincorporated.

2) Micro-Crystal Formulation

Crystallization is performed in any suitable organic solvent forre-crystallisation, such as isopropanol, at an appropriate temperaturesuch as e.g. between +70° C. and −20° C. A hydrocolloid (e.g. HPMC) or asurfactant (e.g. polysorbate) can be used at an appropriateconcentration to manipulate the growth of the crystals duringrecrystallization. Any granulating/coating excipient, such aspharmaceutically acceptable polymers, may be used e.g. ethylcellulose ata concentration of about 10 to about 50%, especially about 20 to about35%, polymethacryllates such as ammonio methacrylate copolymer type Aand B or methacrylic acid copolymer A and B. As a hydrophilic excipientmention can be made of e.g PEG 400.

3) Capsules and Sachets

A capsule (e.g. a capsule of gelatine, HPMC or a starch derivative) or asachet may be filled with coated micro-crystals or coated granules andif necessary appropriate amounts of filling excipients such assugaralcoholes e.g. mannitol, and/or glidants.

4) Tablets

Tablets may be based on either micro-crystals or granules. When it comesto producing tablets in large scale, especially on a rotary machine,further excipients to increase flow ability or to improvetabletting-behaviour may be needed. As filling and binding excipients,if required, mention can be made of e.g. microcrystalline cellulose,such as Avicel® 102, and cellulose at a concentration of about 1 toabout 60%, crystalline, spray dried or granulated lactose monohydratee.g. Tablettose®, as well as anhydrous lactose monohydrate, at aconcentration of about 5 to about 60%, sugar alcohols, such as sorbitoland mannitol, at a concentration of about 0 to about 40% and modifiedstarch at a concentration of about 0 to about 40%. Furthermoredisintegration agents such as starch and starch-derivates such as sodiumstarch glycolate (at a concentration of about 0.2 to about 10° A)),crospovidone (at a concentration of about 0.2 to about 10%), sodiumcarboxymethylcellulose (at a concentration of about 0.1 to about 10%),glidants such as colloidal anhydrous and hydrous silica (at aconcentration of about 0.2 to about 4%), and lubricants, e.g. magnesiumstearate, calcium behenate, and calciumarachinate (at a concentration ofabout 0.2 to about 3%) or sodium stearyl fumarate (at a concentration ofabout 1 to about 8%) can be added.

Dosage

Apart from providing compositions having different content of fumaricacid present, the invention also provides e.g. kits containing two ormore containers e.g. with compositions having various amounts of thefumaric acid included. Such kits are suitable for use in thosesituations where an increasing dosage is required over time. A normalup-scale of the dosage is given below:

Week Morning Noon Evening Strength 1 1 — — A 2 1 — 1 A 3 1 — 1 B 4 1 — —B 5 1 — 1 B 6 1 1 1 B 7 2 1 1 B 8 2 1 2 B 9 2 2 2 B

A corresponds to a low strength such as about 30 mg dimethylfumarate (ora corresponding effective dose of another fumaric acid ester)

B corresponds to a higher strength such as about 120 mg dimethylfumarate(or a corresponding effective dose of another fumaric acid ester)

In one aspect of the invention a controlled release pharmaceuticalcomposition, wherein the amount of one or more fumaric acid estersselected from di-(C₁-C₅)alkylesters of fumaric acid andmono-(C₁-C₅)alkylesters of fumaric acid, or a pharmaceuticallyacceptable salt thereof, in a dosage form is from 90 mg to 360 mg activesubstance, such as 90, 120, 180, 240 or 360 mg active substance, isprovided. In a further aspect of the invention the amount of activesubstance is 120, 180 or 240 mg active substance. In yet a furtheraspect of the invention, the amount of active substance is 180 or 360mg.

The daily dosage of the controlled release pharmaceutical compositionaccording to the invention that is administered to treat a patientdepends on a number of factors among which are included, withoutlimitation, weight and age and the underlying causes of the condition ordisease to be treated, and is within the skill of a physician todetermine. In one aspect of the invention the daily dosage can be e.g.from 240 to 360 mg active substance given in one to three doses, inanother aspect from 360 to 480 mg active substance given in one to threedoses, in another aspect 480 to 600 mg active substance given in one tothree doses, in another aspect 600 to 720 mg active substance given inone to three doses, in another aspect 720 to 840 mg active substancegiven in one to three doses, in another aspect 840 to 960 mg activesubstance given in one to three doses and in yet another aspect 960 to1080 mg active substance given in one to three doses.

In one aspect of the invention the controlled release pharmaceuticalcomposition is in the form of a capsule.

In another aspect of the invention the controlled release pharmaceuticalcomposition in the form of a tablet is provided, such as a tablet whichhas a shape that makes it easy and convenient for a patient to swallowe.g. a tablet which has a rounded or a rod-like shape without any sharpedges.

In another aspect of the invention a pharmaceutical composition in theform of a tablet designed to be divided into two or more parts, isprovided.

The compositions according to the invention may be administered togetherwith a meal or in relation to a meal such as e.g. in a time periodcorresponding to a range from at least about 30 minutes before a meal toabout 2 hours after the meal, or the composition may be administered atany specific point(s) in time during the day.

In one embodiment, the total daily dose is given at bedtime, such as upto or about 30 minutes before bedtime, up to or about 60 minutes beforebedtime, up to or about 90 minutes before bedtime, up to or about 120minutes before bedtime or up to or about 180 minutes before bedtime.

The compositions and kits according to the invention are contemplated tobe suitable to use in the treatment of one or more of the followingconditions:

-   -   a. Psoriasis    -   b. Psoriatic arthritis    -   c. Neurodermatitis    -   d. Inflammatory bowel disease, such as        -   i. Crohn's disease        -   ii. Ulcerative colitis    -   e. autoimmune diseases:        -   i. Polyarthritis        -   ii. Multiple sclerosis (MS)        -   iii. Juvenile-onset diabetes mellitus        -   iv. Hashimoto's thyroiditis        -   v. Grave's disease        -   vi. SLE (systemic lupus erythematosus)        -   vii. Sjögren's syndrome        -   viii. Pernicious anemia        -   ix. Chronic active (lupoid) hepatitis        -   x. Rheumatoid arthritis (RA)        -   xi. Optic neuritis

Moreover, the novel composition or kit according to the invention may beused in the treatment of

-   -   1. Pain such as radicular pain, pain associated with        radiculopathy, neuropathic pain or sciatica/sciatic pain    -   2. Organ transplantation (prevention of rejection)    -   3. Sarcoidosis    -   4. Necrobiosis lipoidica    -   5. Granuloma annulare

Psoriasis has been proposed to potentially be associated with Crohn'sdisease (Najarian D J, Gottlieb A B, Connections between psoriasis andCrohn's disease. J Am Acad Dermatol. 2003 June; 48(6):805-21), celiacdisease (Ojetti V et al, High prevalence of celiac disease in psoriasis.Am J Gastroenterol. 2003 November; 98(11):2574-5.), psychiatric orpsychological disease, such as depression or a life crisis (Gupta M A,Gupta A K, Psychiatric and psychological co-morbidity in patients withdermatologic disorders: epidemiology and management. Am J Clin Dermatol.2003; 4(12):833-42. and Mallbris L et al, Psoriasis phenotype at diseaseonset: clinical characterization of 400 adult cases. J Invest Dermatol.2005 March; 124(3):499-504.), overweight, diabetes mellitus, excessconsumption of alcohol/alcoholism, as well as psoriatic arthritis.

The present invention thus relates in one aspect to a method of treatingpsoriasis, psoriatic arthritis, neurodermatitis, inflammatory boweldisease, such as Crohn's disease and ulcerative colitis, autoimmunediseases, such as polyarthritis, multiple sclerosis (MS), juvenile-onsetdiabetes mellitus, Hashimoto's thyroiditis, Grave's disease, SLE(systemic lupus erythematosus), Sjögren's syndrome, Pernicious anemia,Chronic active (lupoid) hepatitis, Rheumatoid arthritis (RA) and opticneuritis, pain such as radicular pain, pain associated withradiculopathy, neuropathic pain or sciatica/sciatic pain, organtransplantation (prevention of rejection), sarcoidosis, necrobiosislipoidica or granuloma annulare, which method comprises administeringorally to a patient in need thereof, an effective dosage of a controlledrelease pharmaceutical composition according the invention.

The present invention relates in another aspect to the use of acontrolled release pharmaceutical composition according to the inventionfor the preparation of a medicament for the treatment of psoriasis,psoriatic arthritis, neurodermatitis, inflammatory bowel disease, suchas Crohn's disease and ulcerative colitis, autoimmune diseases, such aspolyarthritis, multiple sclerosis (MS), juvenile-onset diabetesmellitus, Hashimoto's thyroiditis, Grave's disease, SLE (systemic lupuserythematosus), Sjögren's syndrome, Pernicious anemia, Chronic active(lupoid) hepatitis, Rheumatoid arthritis (RA) and optic neuritis, painsuch as radicular pain, pain associated with radiculopathy, neuropathicpain or sciatica/sciatic pain, organ transplantation (prevention ofrejection), sarcoidosis, necrobiosis lipoidica or granuloma annulare.

Furthermore, the invention also relates to treating an individualsuffering from one of the conditions in the abovementioned lists, morespecifically psoriasis or psoriatic arthritis, with a composition or kitaccording to the invention, said individual further being in treatmentwith

a) a topical anti-psoriatic drug such as 1) vitamin D or derivativesthereof (calcipotriol, calcipotriene), 2) a corticosteroid (such as e.g.betamethasone, desoximethasone, fluocinolone, momethasone,hydrocortisone aceponate, fluticasone, clobethasol, clobethasone,hydrocortisone butyrate, desonide, triamcinolone or hydrocortisone), 3)tazaroten, 4) ditranol, 5) tacrolimus (FK-506), and other calcineurininhibitors, such as pimecrolimus or 6) any combination of 1-5 and/or

b) an oral anti-psoriatic drug such as 1) an oral retinoid (such asacitretin or etretinate) combined or not combined with PUVA, 2)cyclosporine and other calcineurin inhibitors, such as ISA247,tacrolimus and pimecrolimus, 3) methotrexate, 4) hydroxyurea, 5)azathioprine, 6) sulphasalazine, 7) a fumarate derivative (such as e.g.Fumaderm® or BG-12), 8) rosiglitazone (Avandia) and other peroxisomeproliferator-activated-γ (PPARγ) agonists or modulators, such aspioglitazone, farglitazar, GW1929, GW7845, MC-555, MBX-102/MBX-10,MBX-1828, MBX-2044, CLX-0921, R-483, reglitazar, naveglitazar(LY-519818/LY-818), netoglitazone (MCC-555), CS-7017, troglitazone,ciglitazone, tesaglitazar, isaglitazone, balaglitazone, muraglitazar,TAK-654, LBM642, DRF 4158, EML 4156, T-174, TY-51501, TY-12780, VDO-52or AMG-131(T131) or any combination of 1-8 and/or

c) a parenterally administered anti-psoriatic drug such as 1) alefacept(Amevive), 2) etanercept (Enbrel), 3) efalizumab (Raptiva), 4) onercept,5) adalimumab (Humira) or any combination of 1-5 and/or

d) an inhibitor of TNF-α not mentioned in the list under section c)above (e.g. CDP 870 or infliximab (Remicade)), administered via anenteral or parenteral route and/or

e) tisocalicitrate and/or NCX 1022 and/or IDEC-131 and/or MEDI-507,and/or

f) An NSAID or a COX or a LOX inhibitor such as e.g. a COX-2 inhibitoror a COX/5-LOX inhibitor, and/or

g) an anti-diabetic or anti-obesity drug, such as biguanides such asmetformin; metformin XR; a sulphonylurea such as chlorpropamide,glipizide, gliclazide, glyburide/glibenclamide or glimepiride;Glucovance (metformin+glyburide); Metaglip (glipizide+metformin); aperoxisome proliferator-activated-γ (PPARγ) agonist or modulator, suchas rosiglitazone (Avandia), pioglitazone, farglitazar, GW1929, GW7845,MC-555, MBX-102/MBX-10, MBX-1828, MBX-2044, CLX-0921, R-483, reglitazar,naveglitazar (LY-519818/LY-818), netoglitazone (MCC-555), CS-7017,troglitazone, ciglitazone, tesaglitazar, isaglitazone, balaglitazone,muraglitazar, TAK-654, LBM642, DRF 4158, EML 4156, T-174, TY-51501,TY-12780, VDO-52 or AMG-131(T131); Avandamet (rosiglitazone+metformin);Actos (pioglitazone+metformin); Avandaryl (rosiglitazonemaleate+glimepiride); a benzoimidazole such as FK-614; CS-917; TA-1095;ONO-5129; TAK-559; TAK-677/AJ-9667; a d-phenylalanine inducer such assenaglinide; c-3347; NBI-6024; ingliforib; BVT 3498; LY 929; SGLT2inhibitors; CS 011; BIM 51077; R1438; R1439; R1440; R1498; R1499; AVE0847; AVE 2268; AVE 5688; AVE 8134; TA-6666; AZD 6370; SSR 162369;TLK-17411; NN 2501; MK 431; KGA-2727; MK-767; CS-872; a beta-3 receptorantagonist such as N-5984; an alpha-glucosidase inhibitor such asacarbose, voglibose or miglitol; a glinitide/meglitinide analogue orcarbamoylmethylbensoeic acid derivative such as mitiglinide, repaglinideor nateglinide; a DPP-IV inhibitor such as LAF 237 (vildagliptin),DPP728, P93/01, P32/98, PT-630 or saxagliptin; GLP-1 or GLP-1 analogues,such as exenatide, Exenatide-LAR, liraglutide (NN 2211), ZP 10/AVE 0010,LY 307161, betatropin, CJC-1131, GTP-010, SUN E7001 or AZM 134;pramlinitide acetate; insulin or insulin analogues, such as Humalog(insulin lispro), Humulin, Novolin, Novolog/NovoRapid (insulin aspart),Apidra (insulin glulisine), Lantus (insulin glargine), Exubera,Levemir/NN 304 (insulin detemir), AERx/NN 1998, Insuman, Pulmonaryinsulin or NN 344; sibutramine or other blockers of the presynapticreuptake of serotonin and noradrenalin; orlistat and other inhibitors ofGI lipases; β3-adrenergic receptor agonists; uncoupling proteins;(specific) antagonists of PPARγ (Peroxisome Proliferator-ActivatedReceptor γ); insulin secretagogues; rimonabant and other CB1endocannabinoid receptor antagonists; bupropion; topiramate; leptinagonists; ciliary neurotrophic factor; peptide analogues of the humangrowth hormone fragment 177-191; cholecystokinin-A receptor agonists;melanocortin-3 agonists; noradrenergic drugs such as phentermine,diethylpropion, phendimetrazine or benzphetamine; or any combination ofthe anti-diabetic or anti-obesity drugs mentioned above, and/or

h) a drug potentially useful in the treatment of substance abuse e.g.alcohol abuse such as naltrexone, acamprosate, disulphiram or Vivitrex(naltrexone long acting injection), and/or,

i) a drug potentially useful in the treatment of Crohn's disease such as

-   -   1. 5-ASA compounds such as sulfasalazine, oral 5-ASA        formulations or rectal 5-ASA formulations,    -   2. glucocorticosteroids such as systemic steroids (e.g.        budesonide or prednisolone) or topically acting steroids (e.g.        budesonide),    -   3. antibiotics such as metronidazole or quinolones (e.g.        ciprofloxacine, ofloxacine, norfloxacine, levofloxacine or        moxifloxacine),    -   4. immunosuppressives such as azathioprine, 6-mercaptopurine or        methotrexate,    -   5. nutritional therapies such as elemental or polymeric formulas        or pre- and probiotics,    -   6. biological therapies e.g. TNF-α inhibitors such as        infliximab, adalimumab, CDP870, CDP571, etanercept or onercept,    -   7. symptomatic agents such as anti-diarrheals or        anti-spasmodics.

Examples of suitable NSAIDs are piroxicam, diclofenac, nabumetone,propionic acids including naproxen, flurbiprofen, fenoprofen, ketoprofenand ibuprofen, fenamates including mefenamic acid, paracetamol,indomethacin, sulindac, meloxicam, apazone, pyrazolones includingphenylbutazone, salicylates including aspirin.

Examples of suitable COX-2 inhibitors are rofecoxib (Vioxx), valdecoxib(Bextra), celecoxib (Celebrex), etoricoxib (Arcoxia), lumiracoxib(Prexige), parecoxib (Dynastat), deracoxib (Deram), tiracoxib,meloxicam, nimesolide,(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyrancarboxylic acid (CT-3), 2(5H)-Furanone, 5,5-dimethyl (1-methylethoxy)[4(methylsulfonyl)phenyl]-(DFP); Carprofen (RIMADYL),(Acetyloxy)-benzoic acid, 3-[(nitrooxy)methyl]phenyl ester (NCX4016),P54 (CAS Reg. No. 130996 0) 2,6-Bis(1,1-dimethylethyl)[(E)-(2-ethyl-1,1-dioxo isothiazolidinylidene)methyl]phenoI (S-2474),5(R)-Thio sulfonamide-3(2H)-benzofuranone (SVT-2016) andN-[3-(Formyl-amino) oxo phenoxy-4H benzopyran yl]methanesulfonamide(“T-614”); or a pharmaceutically acceptable salt thereof.

Examples of suitable COX/5-LOX inhibitors are licofelone (ML-3000 or[2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3,dihydro-1H-pyrrolizine-5-yl]-aceticacid), di-tert-butylphenols, such as(E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidence)-2-ethyl-1,2-isothiazolidine-1,1-dioxide(S-2474), darbufelone or tebufelone and pharmacologically activemetabolites as well as derivatives such as dihydro-dimethyl-benzofuranand PGV-20229, dihydro-dimethyl-benzofuran, thiophene derived compoundssuch as RWJ-63556,N-hydroxy-N-methyl-4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl)-butanamide(S19812), methoxytetrahydropyran derivatives, oxygenated xanthones suchas 1,3,6,7-Tetrahydroxyxanthone (norathyriol)-pyrazole thiocarbamates,pyrazoles such as modified forms of phenidone containing compounds orthe tri-fluoro-benzole substituted pyrazoline derivative BW-755C,tepoxaline and derivatives and di-tert-butylpyrimidines.

It is contemplated that such combination therapy leads to an improvedtherapeutic response and/or an increased convenience for the individual,compared to said individual being treated without the composition or kitaccording to the invention.

In a further aspect, the invention relates to a method of reducing sideeffects associated with oral treatment of any of the conditions a-e and1-5 listed above, in which method the active pharmaceutical ingredientfor treating said condition is used in combination with one or more ofthe following agents:

a) an antacid such as 1) magnesium hydroxide, 2) magnesium trisilicate,3) aluminium hydroxyde gel, 3) sodium hydrogencarbonate, 4) magaldrat orany combination of 1-5 and/or

b) a histamine H-2 antagonist such as 1) cimetidine, 2) ranitidine, 3)nizatidine, 4) famotidine, 5) roxatidine, 6) lafutadine or anycombination of 1-6 and/or

c) a cytoprotective agent such as 1) sucralfate, 2) tripotassiumdictitratobismuthate, 3) carbenoxolone, 4) prostaglandin E-2 analoguessuch as misoprostol, 5) ecabet, 6) cetraxate HCl, 7) teprenone, 8)troxipide, 9) dicyclomine hydrochloride, 10) sofalcon or any combinationof 1-10 and/or

d) a proton pump inhibitor (PPI) such as 1) omeprazole, 2) esomeprazole,3) lansoproazole, 4) pantoprazole, 5) rabeprazole, 6) CS-526/R-105266,7) AZD 0865, 8) soraprazan or any combination of 1-8, and/or

e) an NSAID or a COX or a LOX inhibitor such as e.g. a COX-2 inhibitoror a COX/5-LOX inhibitor, and/or

f) pentoxifylline, e.g. at a dose range of from 400 to 800 mg/day.

In a specific embodiment, the active substance is a fumaric acid estercontaining compound. In particular, the fumaric ester containingcompound is any and all of the salts contained in Fumaderm® or Fumaraat®or Panaclar® (BG-12) or described in U.S. Pat. No. 6,277,882, U.S. Pat.No. 6,355,676 or U.S. Pat. No. 6,509,376 or a formulation according tothe present invention. The active pharmaceutical ingredient may beprovided in a formulation according to the present invention, or anyFumaderm® or Fumaraat® or Panaclar® formulation or as e.g. described inU.S. Pat. No. 6,277,882, U.S. Pat. No. 6,355,676 or U.S. Pat. No.6,509,376.

It is to be understood that this invention is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims. Where a range of values is provided, it isunderstood that each intervening value, to the tenth of the unit of thelower limit unless the context clearly dictates otherwise, between theupper and lower limit of that range and any other stated or interveningvalue in that stated range is encompassed within the invention. Theupper and lower limits of these smaller ranges may independently beincluded in the smaller ranges and are encompassed within the invention,subject to any specifically excluded limit in the stated range. Wherethe stated range includes one or both of the limits, ranges excludingeither or both of those included limits are also included in theinvention. Unless defined otherwise, all technical and scientific termsused herein have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Although anymethods and materials similar or equivalent to those described hereincan also be used in the practice or testing of the present invention,the preferred methods and materials are described. All publicationsmentioned herein are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. It must be noted that as used herein and in theappended claims, the singular forms “a”, “an”, and “the” include pluralreferents unless the context clearly dictates otherwise. The patents andpublications discussed herein are provided solely for their disclosureprior to the filing date of the present application. Nothing herein isto be construed as an admission that the present invention is notentitled to antedate such patent or publication by virtue of priorinvention. Further, the dates of publication provided may be differentfrom the actual publication dates which may need to be independentlyconfirmed. As will be apparent to those of skill in the art upon readingthis disclosure, each of the individual embodiments described andillustrated herein has discrete components and features which may bereadily separated from or combined with the features of any of the otherseveral embodiments without departing from the scope or spirit of thepresent invention. The figures shown herein are not necessarily drawn toscale, with some components and features being exaggerated for clarity.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

EXAMPLES Example 1 Preparation of Tablets

200 g granules are mixed with 150 g microcrystalline cellulose (e.g.Avicel® 102), 97.5 g lactose (e.g. Tablettose®), 10 g sodiumcarboxymethylcellulose (e.g. Ac-Di-Sol®) and 25 g starch for 30 min.Then 10 g magnesium stearate and 7.5 g amorphous silicium dioxide (e.g.Aerosil® 200) is added and the powder mixture is mixed for 5 min.

This powder mixture is compressed to tablets in tabletting equipment(tablet diameter 10 mm, surface about 280-300 mm²). The tablets areenteric coated in a pan-coating or in a fluid-bed coating process asdescribed in Example 4.

Example 2 Preparation of Tablets

200 g micro-crystals are mixed with 150 g microcrystalline cellulose(e.g. Avicel® 102), 130 g lactose (e.g. Tablettose®), 10 g of sodiumcarboxymethylcellulose (e.g. Ac-Di-Sol®) and 25 mg starch for 30 min.Then 10 g magnesium stearate and 7.5 g of amorphous silicium dioxide isadded and the powder mixture is mixed for 5 min. This powder mixture iscompressed to tablets in tabletting equipment (tablet diameter 10 mm,surface about 280-300 mm²). The tablets are enteric coated in apan-coating or in a fluid-bed coating process as described in Example 4.

Example 3 Preparation of Capsules

Granules or micro-crystals are filled in HPMC capsules and thesecapsules are enteric coated as described in the following. In a pancoater Eudragit® L30D-55 is sprayed at drying temperatures of 60° C. to80° C. onto the capsules in an amount of 20 mg polymeric material permm². Pigments and talc are added in an appropriate amount.

Example 4 Enteric Coating of Tablets

In a pan coater Eudragit® L30D-55 is sprayed at drying temperatures of60° C. to 80° C. onto the tablets in an amount of 6 mg polymericmaterial per mm². Pigments and talc are added in an appropriate amount.

Example 5 Preparation of Capsules

156 mg of micro-crystals, prepared as described in Example 15, is filledin a hard-gelatine-capsule size 0. The capsules are enteric coated bydipping them into a solution of 5% HPMCP (Pharmacoat HP 50®) in acetonefour times each capsule-side.

Example 6 Preparation of Granules

In a granulation process 50 g dimethylfumarate (in the following DMF) ismixed with 1 g ethyl cellulose (e.g. Ethocel® NF premium) which isdissolved in 10 ml ethanol 96%, passed through a sieve 1.0 mm and driedat 50° C. to 60° C. for 30 min. These granules are manufactured totablets and capsules using the same process as described in Examples 1and 3.

Example 7 Preparation of Granules

In a granulation process 50 g DMF is mixed with 1 g polyvinylacetate(PVA) (e.g. Kollicoat® SR30) which is dissolved in 10 ml ethanol 96%,passed through a sieve 1.00 mm and dried at 50° C. to 60° C. for 30 min.

Example 8 Preparation of Granules

In a granulation process 50 g DMF is mixed with 15 g of powderedEudragit® RL 100. After adding an appropriate amount of 2-propanol andpassing through a 1.00 mm sieve, the granules are dried at 60° C. Thesegranules are manufactured to tablets and capsules using the same processas described in Examples 1 and 3.

Example 9 Preparation of Coated Granules

In a granulation process 50 g DMF is directly mixed with 5 g Eudragit®RL30D, passed through a sieve (1.00 mm) and dried at 80° C. Aftersieving the granules are coated in a fluid-bed coater (Mini-Glatt) with15 g of a 1:1 mixture Eudragit® RL30D/RS30D. The coated granules can bemanufactured to tablets and capsules using the same process as describedin Examples 1 and 3.

Example 10 Preparation of Coated Granules

In a granulation process 50 g DMF is mixed with 20% ethyl cellulose(e.g. Ethocel® NF premium) which is dissolved in an appropriate amountof ethanol 96%. 15% polyethylene glycole 6000 are added to thegranulation liquid. The mixture is passed through a sieve 1.00 mm anddried at 50° to 60° C. for 30 min. After sieving the granules are coatedin a fluid-bed coated (Mini-Glatt) with a 2:1 mixture of ethyl celluloseand polyethylene glycole 6000 in an amount of 20 mg per mm² granulessurface area. These granules can be manufactured to tablets or capsulesusing the processes described in Examples 1 and 3.

Example 11 Preparation of Coated Granules

In a granulation process 50 g DMF is mixed with 10% ethyl cellulose(e.g. Ethocel® NF premium) which is dissolved in an appropriate amountof ethanol 96%. 6% povidone (e.g. Kollidon® 25) is added to thegranulation liquid. The mixture is passed through a sieve 1.00 mm anddried at 50° to 60° C. for 30 min. After sieving the granules are coatedin a fluid-bed coated (Mini-Glatt) with a 3:2 mixture of ethyl celluloseand povidone in an amount of 20 mg per mm² granule surface area.

These granules can be manufactured to tablets or capsules using theprocesses described in Examples 1 and 3.

Example 12 Preparation of Coated Granules

In a granulation process 50 g DMF is mixed with 10% ethyl cellulose(e.g. Ethocel® NF premium) which is dissolved in an appropriate amountof ethanol 96%. 5% hydroxypropyl cellulose (HPC) (e.g. Klucel®) areadded to the granulation liquid. The mixture is passed through a sieve1.00 mm and dried at 50° to 60° C. for 30 min. After sieving, thegranules are coated in a fluid-bed coater (mini-Glatt) with a 2:1mixture of ethyl cellulose and HPC in an amount of 20 mg per mm² granulesurface area.

These granules can be manufactured to tablets or capsules using theprocesses described in Examples 1 and 3.

Example 13 Preparation of Coated Granules

In a granulation process 50 g DMF is directly mixed with an appropriateamount of an aqueous dispersion of Eudragit® NE30D, passed through asieve (1.00 mm) and dried at 80° C. After sieving the granules arecoated in a fluid-bed coater (Mini-Glatt) with 15 g of a 1:1 mixtureEudragit® RL30D/RS30D. The coated granules can be manufactured totablets and capsules using the processes described in Examples 1 and 3.

Example 14 Preparation of Coated Granules

In a granulation process 50 g DMF is directly mixed with an appropriateamount of an aqueous dispersion of Eudragit® RL30D, passed through asieve (1.00 mm) and dried at 80° C. After sieving, the granules arecoated in a fluid-bed coater (Mini-Glatt) with Eudragit® NE30D. Thecoated granules can be manufactured to tablets and capsules using theprocesses described in Examples 1 and 3.

Example 15 Preparation of Coated Micro-Crystals

A saturated solution of 50 g DMF in 300 ml 2-propanol is prepared at 60°C. and slowly cooled under permanent stirring. The precipitated crystalsare filtered off and dried at 50° C. The crystals are sieved and the315-710 μm fraction is used for a coating process in either a pan coateror a fluid-bed coater (Mini-Glatt). A coating solution of 12 g ethylcellulose (e.g. Ethocel® NF premium) and 3 g polyethylene glycole 400 in500 g ethanol is sprayed at 60° C. onto the powder surface. Afterdrying, the coated crystals are sieved through a 1.00 mm sieve. Thesecoated DMF crystals can be manufactured to tablets and capsules usingthe processes described in Examples 2 and 3.

Example 16 Preparation of Tablets

In a granulation process 50 g DMF is mixed with 12 g Ethylcellulose(e.g. Ethocel® NF premium) and 3 g Polyethylenglycole 400 which isdissolved in 150 ml Ethanol 96%, passed through a 1.0 mm sieve, dried at50° to 60° C. over 30 min and again passed through a sieve 1.0 mm. Aplacebo granulate is prepared as follows: Tablettose® and Avicel® 102are mixed in equal shares and granulated with 2% povidone (e.g.Kollidon® 25) dissolved in water (q.s.), passed through a 1.0 mm sieve,dried at 50° to 60° C. over 30 min and again passed through a 1.0 mmsieve. 60 parts of the DMF-granulate and 38 parts of theplacebo-granulate are mixed for 30 minutes in a Turbula Shaker Mixer.One part Aerosil® 200 and one part magnesium stearate are added and theblend is mixed again for 5 minutes. The blend is compressed to tabletswith a diameter of 10 mm, a weight of about 260 mg and a hardness ofabout 50 N. The tablets are enteric coated using the processes describedin Example 4.

Example 17 Preparation of Tablets

In a granulation process 50 g DMF is mixed with 12 g Ethylcellulose(e.g. Ethocel® NF premium) and 3 g Polyethylenglycole 400 which isdissolved in 150 ml Ethanol 96%, passed through a 1.0 mm sieve, dried at50° to 60° C. over 30 min and again passed through a sieve 1.0 mm. Aplacebo granulate is prepared as follows: Tablettose® and Avicel® 102are mixed in equal shares and granulated with 2% povidone (e.g.Kollidon® 25) dissolved in water (q.s.), passed through a 1.0 mm sieve,dried at 50° to 60° C. over 30 min and again passed through a 1.0 mmsieve. 60 parts of the DMF-granulate and 37 parts of theplacebo-granulate are mixed for 30 minutes in a Turbula Shaker Mixer.One part carboxymethylcellulose (e.g. Ac-Di-Sol®), one part Aerosil® 200and one part magnesium stearate are added and the blend is mixed againfor 5 minutes.

The blend is compressed to tablets with a diameter of 10 mm, a weight ofabout 260 mg and a hardness of about 50 N. The tablets are entericcoated using the processes described in Example 4.

Example 18 Preparation of Coated Micro-Crystals

A saturated solution of 50 g DMF in 300 ml 2-propanol is prepared at 60°C. and slowly cooled under permanent stirring. The precipitated crystalsare filtered off and dried at 50° C. The crystals are sieved and the315-710 μm fraction is used for a coating process in either a pan coateror a fluid-bed coater (Mini-Glatt). A coating solution of 12 g ethylcellulose (e.g. Ethocel® NF premium) and 3 g povidone (PVP) in 500 gethanol is sprayed at 60° C. onto the surface of the crystals. Afterdrying the coated crystals are sieved through a 1.00 mm sieve. Thecoated DMF crystals can be manufactured to tablets and capsules usingthe processes described in Example 2 and 3.

Example 19 Preparation of Coated Micro-Crystals

A saturated solution of 50 g DMF in 300 ml 2-propanol is prepared at 60°C. and slowly cooled under permanent stirring. The precipitated crystalsare filtered off and dried at 50° C. The crystals are sieved and the315-710 μm fraction is used for a coating process in either a pan coateror a fluid-bed coater (Mini-Glatt). A coating solution of 12 g ethylcellulose (e.g. Ethocel® NF premium) and 3 g hydroxylpropylcellulose(HPC) in 500 g ethanol is sprayed at 60° C. onto the powder surface.After drying the coated crystals are sieved through a 1.00 mm sieve.These coated DMF crystals can be manufactured to tablets and capsulesusing the processes described in Examples 2 and 3.

Example 20 Preparation of Micro-Crystals

DMF-crystals are prepared as described in Example 15, but 2% of ethylcellulose, related to the mass of the crystals, is added directly to the2-propanol before precipitation of the crystals.

Example 21 Preparation of Coated Micro-Crystals

50 g DMF crystals prepared as described in Example 15 are coated in afluid-bed coater (Mini-Glatt) at a temperature of 80° C. with 20 g of anaqueous dispersion of a 1:1 mixture of Eudragit® RL30D/RS30D. Thesecoated DMF crystals are manufactured to tablets and capsules using theprocesses described in Examples 2 and 3.

Example 22 Preparation of Tablets

DMF crystals prepared as described in Example 15 are directly mixed with25% solid Eudragit® RS PO/RL PO in a ratio of 1:2 and manufactured totablets as described in Example 2.

Example 23 Preparation of Coated Micro-Crystals

DMF crystals prepared as described in Example 15 are coated in afluid-bed coater (Mini-Glatt) with an amount of 5% (related to the massof the crystals) aqueous dispersion of polyvinyl acetate (e.g.Kollicoat® SR 30D). These coated DMF crystals can be manufactured totablets and capsules using the processes described in Examples 2 and 3.

Example 24 Preparation of Granules

In a granulation process, 50 g DMF is mixed with 15% ethyl cellulose(e.g. Ethocel® NF premium) which is dissolved in an appropriate amountof ethanol 96%. 10% polyethylene glycole 6000 is added to thegranulation liquid. The mixture is passed through a sieve 1.00 mm anddried at 50° to 60° C. for 30 min. These granules can be manufactured totablets or capsules using the processes described in Examples 1 and 3.

Example 25 Preparation of Granules

In a granulation process, 50 g diethylfumarate (DEF) is mixed with 15%ethyl cellulose (e.g. Ethocel® NF premium) which is dissolved in anappropriate amount of ethanol 96%. 10% polyethylene glycole 6000 isadded to the granulation liquid. The mixture is passed through a sieve1.00 mm and dried at 50° to 60° C. for 30 min. These granules can bemanufactured to tablets or capsules using the processes described inExamples 1 and 3.

Example 26 Preparation of Tablets

A granulate is prepared as described in Example 24 but instead of PEG6000, 10% of povidone (e.g. Kollidon® 25) is added. This mixture can bemanufactured to tablets or capsules using the processes described inExamples 1 and 3.

Example 27 Preparation of Tablets

A granulate is prepared as described in Example 24 but instead of PEG6000, 10% hydroxyl propyl methylcellulose is added. This mixture can bemanufactured to tablets or capsules using the processes described inExamples 1 and 3.

Example 28

50 g DMF crystals prepared as described in Example 15 are coated in afluid-bed coater (Mini-Glatt) at a temperature of 80° C. with 20 g of anaqueous dispersion of a 1:1 mixture of Eudragit® RL30D/RS30D. The coatedcrystals are enteric coated in a pan coater as described in thefollowing. Eudragit® L30D-55 are sprayed at drying temperatures of 60°C. to 80° C. onto the coated crystals in an amount of 6 mg polymericmaterial per mm²

These double coated DMF crystals are either filled into hard gelatine orsoft gelatine capsules or manufactured to tablets using the processdescribed in Example 2.

Example 29 Preparation of Tablets

In a granulation process 50 g DMF is mixed with 12 g Ethylcellulose(e.g. Ethocel® NF premium) and 3 g hydroxypropyl cellulose (e.g.Klucel®) which is dissoloved in 150 ml Ethanol 96%, passed through asieve 1.0 mm, dried at 50° to 60° C. over 30 min and again passedthrough a sieve 1.0 mm.

Tablettose® and Avicel® 102 are mixed in equal shares and granulatedwith 2% povidone (Kollidon® 25) dissolved in water (q.s.). 60 parts ofthe DMF-granulate and 38 parts of the placebo-granulate are mixed for 30minutes in a Turbula Shaker Mixer. One part Aerosil® 200 and one partmagnesium stearate are added and the blend is mixed again for 5 minutes.The blend is compressed to tablets with a diameter of 10 mm, a weight ofabout 260 mg and a hardness of about 50 N. The tablets are entericcoated using the process described in Example 4.

Example 30 Determination of pH Controlled Release Dissolution Profile ofCapsules

The dissolution profile is determined as described in the United StatesPharmacopoeia using a rotating basket with 6 so called Levy-glasses witha capacity of 1 liter and 6 basket stirring elements powered by anelectric motor (at 100 rpm). The Levy-glasses are filled with 0.1N HCl(the water bath has a temperature of 37° C.+/−0.5° C.) and the capsulesare applied to the baskets. After 2 hours, the acid is removed from thevessels and replaced with dissolution medium (USP phosphate buffer, pH6.5) and tested for another 6 hours. Samples (5 ml) are taken after 0,60 and 120 minutes from the acid medium, and after 30, 60, 90, 120, 180,240, 300 and 360 minutes from the buffer medium after replacing thedissolution medium with USP buffer. Instead of replacing the amount ofdrawn buffer solution after each sample, the loss of buffer is takeninto account when calculating the amount of released DMF. The amount ofDMF is determined by HPLC (Kontron XXX) using a Merck LiChroCART RP8 5μM, 20 cm column, tempered at 25° C. The mobile phase consists of amixture (35:65) of acetonitrile and 0.0725 mol/l NaH₂PO₄*H₂O-bufferadjusted to pH 3.2 with phosphoric acid. The UV detector is set at awavelength of 230 nm and a flow rate of 1.0 ml per minute. The DMF peakis detectable after a retention time of about 5 min.

Example 31 Determination of pH Controlled Release Dissolution Profile ofNon-Enteric Coated Tablets

The dissolution profile is determined using 6 so called Levy-glasseswith a capacity of 1 liter and 6 paddles as stirring elements powered byan electric motor. The rotating speed of the paddles is 100 rpm. TheLevy-glasses are filled with USP phosphate buffer, pH 6.5 (the waterbath has a temperature of 37° C.+/−0.5° C.) and the tables are into theLevy-glasses. Samples (5 ml) are taken after 0, 30, 60, 90, 120, 180,240, 300 and 360 minutes from the buffer medium after replacing thedissolution medium with USP buffer. Instead of replacing the amount ofdrawn buffer solution after each sample, the loss of buffer is takeninto account when calculating the amount of released DMF. The amount ofDMF is determined by HPLC (Kontron XXX) using a Merck LiChroCART RP8 5μM, 20 cm column, tempered at 25° C. The mobile phase consists of amixture (35:65) of acetonitrile and 0.0725 mol/l NaH₂PO₄*H₂O-bufferadjusted to pH 3.2 with phosphoric acid. The UV detector is set at awavelength of 230 nm and a flow rate of 1.0 ml per minute. The DMF peakis detectable after a retention time of about 5 min.

Example 32

The dissolution profile of capsules prepared as described in Example 5is determined as described in Example 30. The dissolution profile isshown in FIG. 1.

Example 33

The dissolution profile of the tablets (before the enteric coating isapplied) prepared as described in example 16 is determined as describedin Example 31. The dissolution profile is shown in FIG. 2.

Example 34

The dissolution profile of the tablets (before the enteric coating isapplied) prepared as described in example 17 is determined as describedin Example 31. The dissolution profile is shown in FIG. 3.

1. A pharmaceutical composition comprising as an active substance one ormore fumaric acid esters selected from di-(C₁-C₅)alkylesters of fumaricacid and mono-(C₁-C₅)alkylester of fumaric acid, or a pharmaceuticallyacceptable salt thereof, which—upon oral administration and incomparison to that obtained after oral administration of Fumaderm®tablets in an equivalent dosage—gives a reduction in GI related sideeffects. 2-45. (canceled)
 46. A kit comprising: (a) a first unit dosageform consisting essentially of about 120 mg of dimethylfumarate and oneor more pharmaceutically acceptable excipients, wherein thedimethylfumarate is formulated for delayed release; and (b) a secondunit dosage form consisting essentially of about 240 mg ofdimethylfumarate and one or more pharmaceutically acceptable excipients,wherein the dimethylfumarate is formulated for delayed release.
 47. Thekit of claim 46, wherein the first unit dosage form is in the form of acapsule or a tablet.
 48. The kit of claim 47, wherein the capsule is ahard gelatin capsule.
 49. The kit of claim 47, wherein the first unitdosage form comprises microtablets.
 50. The kit of claim 49, wherein themicrotablets are surrounded by an enteric coating.
 51. The kit of claim47, wherein the first unit dosage form comprises pellets.
 52. The kit ofclaim 47, wherein the kit comprises fourteen capsules of the first unitdosage form.
 53. The kit of claim 50, wherein the kit consists offourteen capsules of the first unit dosage form.
 54. The kit of claim46, wherein the pharmaceutically acceptable excipients in the first unitdosage comprise one or more of the following: micro crystallinecellulose, cross-linked sodium carboxymethylcellulose, talc, silicacolloidal silicon dioxide, magnesium stearate, or a surfactant having anHLB value above
 8. 55. The kit of claim 54, wherein the first unitdosage form comprises from about 1 to about 60% micro crystallinecellulose.
 56. The kit of claim 54, wherein the first unit dosage formcomprises from about 0.2 to about 3% magnesium stearate.
 57. The kit ofclaim 54, wherein the first unit dosage form comprises from about 0.2 toabout 4% silica.
 58. The kit of claim 54, wherein the first unit dosageform comprises cross-linked sodium carboxymethylcellulose.
 59. The kitof claim 54, wherein the first unit dosage form comprises a surfactanthaving an HLB value above
 8. 60. The kit of claim 46, wherein the secondunit dosage form is in the form of a capsule or a tablet.
 61. The kit ofclaim 60, wherein the capsule is a hard gelatin capsule.
 62. The kit ofclaim 60, wherein the second unit dosage form comprises microtablets.63. The kit of claim 62, wherein the microtablets are surrounded by anenteric coating.
 64. The kit of claim 60, wherein the second unit dosageform comprises pellets.
 65. The kit of claim 60, wherein the kitcomprises fourteen capsules of the second unit dosage form.
 66. The kitof claim 46, wherein the pharmaceutically acceptable excipients in thesecond unit dosage form comprise at least one of the followingexcipients micro crystalline cellulose, cross-linked sodiumcarboxymethylcellulose, talc, silica colloidal silicon dioxide,magnesium stearate, or a surfactant having an HLB value above
 8. 67. Thekit of claim 66, wherein the second dosage unit comprises from about 1to about 60% micro crystalline cellulose.
 68. The kit of claim 66,wherein the second dosage unit comprises from about 0.2 to about 3%magnesium stearate.
 69. The kit of claim 66, wherein the second dosageunit comprises from about 0.2 to about 4% silica.
 70. The kit of claim66, wherein the second unit dosage comprises cross-linked sodiumcarboxymethylcellulose.
 71. The kit of claim 66, wherein the seconddosage unit comprises a surfactant having an HLB value above
 8. 72. Thekit of claim 46, wherein said first dosage unit and said second dosageunit are produced using dimethylfumarate micro crystals.
 73. The kit ofclaim 72, wherein said micro crystals are surrounded by an entericcoating.
 74. The kit of claim 72, wherein said first unit dosage formand said second unit dosage form are produced using dimethylfumaratemicro crystals between 315 and 710 microns, which are subsequentlycoated with a layer containing an enteric coating polymer.
 75. The kitof claim 46, further comprising a label containing instructions for anoral dosage regimen of (i) and (ii).